New piperidinylamino-thieno[2,3-d] pyrimidine compounds

ABSTRACT

The invention relates to 5-HT receptor antagonists. Novel piperidinylamino-thieno[2,3-d]pyrimidine compounds represented by Formula I, and synthesis and uses thereof for treating diseases mediated directly or indirectly by 5-HT receptors, are disclosed. Such conditions include central nervous system disorders such as anxiety, depression, schizophrenia, neural injury, stroke, and migraine. Methods of preparation and novel intermediates and pharmaceutical salts thereof are also included.

RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C.119(e) to copending U.S. Provisional Application No. 60/458,831, filedon Mar. 31, 2003; the entire contents of which is incorporated herein byreference.

FIELD OF THE INVENTION

[0002] The invention generally relates to the field of serotonin(5-hydroxytryptamine, or 5-HT) receptor modulators, e.g., antagonists,and more particularly to new piperidinylamino-thieno[2,3-d]pyrimidinecompounds which are also 5-HT modulators, and use of these compounds,e.g., in the treatment, modulation and/or prevention of physiologicalconditions associated with serotonin action, such as in treatingvascular disorders, e.g., angina, migraine, pulmonary hypertension andsystemic hypertension.

BACKGROUND OF THE INVENTION

[0003] The serotonergic neural system of the brain has been shown toinfluence a variety of physiologic functions which manifest themselvesin a variety of disorders such as eating disorders, schizophrenia,neuralgia, and addiction disorders; depression, obsessive compulsivedisorders, panic disorders, anxiety, sexual dysfunctions caused by thecentral nervous system and disturbances in sleep and the absorption offood, alcoholism, pain, memory deficits, unipolar depression, dysthymia,bipolar depression, treatment-resistant depression, depression in themedically ill, panic disorder, obsessive-compulsive disorder, eatingdisorders, social phobia, premenstrual dysphoric disorder, pulmonaryhypertension and systemic hypertension.

[0004] 5-HT receptor modulators e.g., antagonists, partial agonists oragonists, and/or selective serotonin reuptake inhibitors (SSRIs) such asfluoxetine, paroxetine, fluvoxamine, sertraline, lorazepam, imipramine,citalopram, and nortriptyline, may be used for the treatment of theabove conditions, as well as for vasodilation, smooth musclecontraction, bronchoconstriction, brain disorders such as vasculardisorders such as angina and migraine; and neuropathological disordersincluding Parkinson's disease and Alzheimer's disease. These compoundsare also suitable for the modulation of the cardiovascular system andpulmonary disorders including pulmonary hypertension and pulmonaryfibrosis. They also intervene in the regulation of the cerebralcirculation and thus represent effective agents for controllingmigraine. They are also suitable for the prophylaxis and control of theeffects of occurrences of cerebral infarct (Apoplexia cerebri) such asstroke or cerebral ischemia. They are also suitable for the control ofdisorders of the intestinal tract which are characterized bydisturbances of the serotoninergic system and also by disturbances ofthe carbohydrate metabolism.

[0005] Trazodone controls 5-HT actions, and fluoxetine and fluvoxaminefacilitate serotoninergic neurotransmission via potent and selectiveinhibition of serotonin reuptake into presynaptic neurons.3-chloroimipramine inhibits both 5-HT and norepinephrine reuptake. Othercompounds of current interest as antidepressants include zimeldine,bupropion and nomifensine.

[0006] Type 2 serotonin inhibitors (5-HT₂) mediate the action of severaldrugs used in treating, e.g., schizophrenia, feeding disorders,perception, depression, migraines, hypertension, anxiety,hallucinations, and gastrointestinal dysfunctions. The 5-HT_(2A, B or C)receptor subtypes show considerable homology at genetic, structural andfunctional levels, and all are G-protein coupled receptors (GPCRs.)5-HT_(2A) receptors have been found in high density in the cerebralcortex and in interneuronal regions, as well as (in lower density) inthe hippocampus, striatum, other cerebral regions, platelets andvascular and uterine smooth muscle. 5-HT_(2B) receptors are widelydistributed in mammalian peripheral tissue, e.g., heart, skeletal andvascular muscle, adipose tissue, intestine, ovary, uterus, testis,liver, lung, pancreas, trachea, spleen, thymus, thyroid, prostate andsalivary gland, as well as in the CNS.

[0007] It is desired to have selective, high affinity, metabolicallystable 5-HT receptor modulators that possess good bioavailability, CNSpenetration, and good pharmacokinetic properties, e.g., in vivo.

SUMMARY OF THE INVENTION

[0008] The present invention relates to the discovery of new compoundswhich are 5-HT modulators, e.g., antagonists, and/or SSRIs, that can beused for treating, preventing or curing 5-HT-related conditions, such asin treating vascular disorders, e.g., angina, migraine, pulmonaryhypertension and systemic hypertension. In particular, it has been foundthat certain piperidinylamino-thieno[2,3-d]pyrimidine compounds areeffective 5-HT receptor modulators and/or SSRIs. In an embodiment, suchcompounds include those having the formula

[0009] wherein

[0010] R₁ and R₂ may independently be hydrogen; lower alkyl, e.g.,straight or branched C₁, C₂, C₃, C₄ or C₅ alkyl; C₁-C₆ cycloalkyl orcycloheteroalkyl; halogens including F, Cl, Br, I, halo-substitutedalkyls such as CF₃, CF₂CF₃, CH₂CF₃; or R₁ and R₂, taken together, form aC₅-C₇ cycloalkyl, e.g., cyclohexyl, or cycloheteroalkyl ring; Cy may bea single or conjugated substituted or unsubstituted alicyclic, e.g.,cycloalkyl, or, desirably, an aromatic ring structure, e.g., phenyl,naphthyl, diphenylmethyl; and n may be 0, 1, 2, 3, 4 or 5; andpharmaceutically acceptable salts and/or esters thereof.

[0011] In an embodiment, R₁ may desirably be H or —CH₃. In anembodiment, R₂ may desirably be lower alkyl, e.g., straight or branchedC₁, C₂, C₃ (e.g., iso- or tert-butyl), C₄ or C₅ alkyl. R₁ and R₂ mayalso, taken together, desirably form a cyclohexyl ring. The linkinggroup denoted by ( )_(n) may be straight or branched.

[0012] Substituents on Cy include mono-, di-, or tri-substituted phenyl,naphthyl, or biphenyl with lower alkyl, e.g., methyl, ethyl, propyl,allyl, n-butyl, n-pentyl, n-hexyl; alkoxy or aryloxy, e.g., methoxy,ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy,cyclopentyloxy; halo, e.g., fluoro, chloro, bromo, and iodo; amino,dimethylamino, nitro, cyano, carboxy, carboxy esters, carboxamides,N-alkylcarboxamide, N.N-dialkylcarboxamide, trifluoromethyl,trifluoromethoxy, tetrazolo, sulphonyl, thiomethyl, thioethyl,phenylthio, 2,3-methylenedioxy, and 3,4-methylenedioxy.

[0013] In another embodiment compounds of the invention include thosehaving the formula

[0014] wherein

[0015] R₁ and R₂ may independently be hydrogen; lower alkyl, e.g., C₁-C₅alkyl; C₁-C₆ cycloalkyl or cycloheteroalkyl; halogens including F, Cl,Br, I, halo-substituted alkyls such as CF₃, CF₂CF₃, CH₂CF₃; or R₁ andR₂, taken together, form a C₅-C₇ cycloalkyl or cycloheteroalkyl ring;

[0016] R₃ and R₄ may independently be Ar which in turn may be a singleor conjugated substituted or unsubstituted aromatic ring structure,e.g., phenyl, naphthyl, diphenylmethyl; (C₁-C₆)alkyl, (C₁-C₇)cyclohexyl,

[0017] R₅ may be H, (C₁-C₅)alkyl, (C₁-C₆)cycloalkyl, halogen substitutedalkyl, NH₂, NHMe, NMe₂, NHEt, NH(Et)₂, NH(Pr), N(Pr)₂, and n may be 0,1, 2, 3, 4 or 5; and pharmaceutically acceptable salts and/or estersthereof.

[0018] Compounds of the invention may also be 5-HT receptor antagonists,e.g., 5-HT₂ receptor antagonists including 5-HT_(2A, B or C) receptors,and desirably 5-HT_(2B) receptor antagonists.

[0019] In another embodiment compounds of the invention may also be 5-HTreceptor partial agonists, e.g., 5-HT₂ receptor partial agonistsincluding 5-HT_(2A, B or C) receptors, and desirably 5-HT_(2B) receptorpartial agonists.

[0020] In another embodiment compounds of the invention may also be 5-HTreceptor agonists, e.g., 5-HT₂ receptor agonists including5-HT_(2A, B or C) receptors, and desirably 5-HT_(2B) receptor agonists.

[0021] Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat depression in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.

[0022] Another aspect of the invention is a method for treatingdepression in a mammal such as a human comprising administering atherapeutically effective amount of a compound according to Formula I.

[0023] Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat diseases of the central nervous system in a mammal sufferingtherefrom, and a pharmaceutically acceptable carrier.

[0024] Another aspect of the invention is a method for treating diseasesof the central nervous system in a mammal such as a human comprisingadministering a therapeutically effective amount of a compound accordingto Formula I.

[0025] Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat pulmonary hypertension in a mammal suffering therefrom, and apharmaceutically acceptable carrier.

[0026] Another aspect of the invention is a method for treatingpulmonary hypertension in a mammal such as a human comprisingadministering a therapeutically effective amount of a compound accordingto Formula I.

[0027] Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat systemic hypertension in a mammal suffering therefrom, and apharmaceutically acceptable carrier.

[0028] Another aspect of the invention is a method for treating systemichypertension in a mammal such as a human comprising administering atherapeutically effective amount of a compound according to Formula I.

[0029] Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective intreating conditions associated with vascular disorders, e.g., angina,migraine, pulmonary hypertension and systemic hypertension.

[0030] Another aspect of the invention is a method of treatingconditions associated with vascular disorders, e.g., angina, migraine,pulmonary hypertension and systemic hypertension.

[0031] Processes for preparing the compounds and novel intermediates arealso included in the invention.

[0032] The invention is also drawn to methods of treating associatedwith serotonergic hypofunction or hyperfunction. As explained above,compounds of the invention can have antagonistic activity at 5-HT_(2B)receptors, which will counteract the negative feedback mechanism inducedby the inhibition of serotonin reuptake; this is thereby expected toimprove the effect of the serotonin reuptake inhibiting activity of thecompounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0033] The features and other details of the invention will now be moreparticularly described with reference to the accompanying drawings andpointed out in the claims. It will be understood that particularembodiments described herein are shown by way of illustration and not aslimitations of the invention. The principal features of this inventioncan be employed in various embodiments without departing from the scopeof the invention. All parts and percentages are by weight unlessotherwise specified.

[0034] Definitions

[0035] For convenience, certain terms used in the specification,examples, and appended claims are collected here.

[0036] “5-HT receptor modulator” or “5-HT modulator” includes compoundshaving effect at the 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆ or 5-HT₇receptors, including the subtypes of each receptor type, such as5-HT_(1A, B, C, D, E or F); 5-HT_(2A, B or C); and 5-HT_(5A or B). 5-HTmodulators may be agonists, partial agonists or antagonists.

[0037] “Treating”, includes any effect, e.g., lessening, reducing,modulating, or eliminating, that results in the improvement of thecondition, disease, disorder, etc.

[0038] “Alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl), branched-chain alkyl groups (e.g.,isopropyl, tert-butyl, isobutyl), cycloalkyl (e.g., alicyclic) groups(e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl),alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkylgroups. “Alkyl” further includes alkyl groups which have oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbonbackbone carbon atoms. In certain embodiments, a straight chain orbranched chain alkyl has six or fewer carbon atoms in its backbone(e.g., C₁-C₆ for straight chain, C₃-C₆ for branched chain), and morepreferably four or fewer. Likewise, preferred cycloalkyls have fromthree to eight carbon atoms in their ring structure, and more preferablyhave five or six carbons in the ring structure. “C₁-C₆” includes alkylgroups containing one to six carbon atoms.

[0039] The term “alkyl” also includes both “unsubstituted alkyls” and“substituted alkyls”, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkyl,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)). “Alkyl” also includes the side chains of natural andunnatural amino acids.

[0040] “Aryl” includes groups with aromaticity, including 5- and6-membered “unconjugated”, or single-ring, aromatic groups that mayinclude from zero to four heteroatoms, as well as “conjugated”, ormulticyclic, systems with at least one aromatic ring. Examples of arylgroups include benzene, phenyl, pyrrole, furan, thiophene, thiazole,isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole,isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and thelike. Furthermore, the term “aryl” includes multicyclic aryl groups,e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole,benzodioxazole, benzothiazole, benzoimidazole, benzothiophene,methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole,benzofuran, purine, benzofuran, deazapurine, or indolizine. Those arylgroups having heteroatoms in the ring structure may also be referred toas “aryl heterocycles”, “heterocycles,” “heteroaryls” or“heteroaromatics”. The aromatic ring can be substituted at one or morering positions with such substituents as described above, as forexample, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings which are not aromatic so as to form amulticyclic system (e.g., tetralin, methylenedioxyphenyl).

[0041] “Alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, but thatcontain at least one double bond. For example, the term “alkenyl”includes straight-chain alkenyl groups (e.g., ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl),branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups(e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, andcycloalkyl or cycloalkenyl substituted alkenyl groups. The term“alkenyl” further includes alkenyl groups which include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbonbackbone carbons. In certain embodiments, a straight chain or branchedchain alkenyl group has six or fewer carbon atoms in its backbone (e.g.C₂-C₆ for straight chain, C₃-C₆ for branched chain.) Likewise,cycloalkenyl groups may have from three to eight carbon atoms in theirring structure, and more preferably have five or six carbons in the ringstructure. The term “C₂-C₆” includes alkenyl groups containing two tosix carbon atoms.

[0042] The term “alkenyl” also includes both “unsubstituted alkenyls”and “substituted alkenyls”, the latter of which refers to alkenylmoieties having substituents replacing a hydrogen on one or morehydrocarbon backbone carbon atoms. Such substituents can include, forexample, alkyl groups, alkynyl groups, halogens, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0043] “Alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond. For example, “alkynyl” includesstraight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chainalkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynylgroups. The term “alkynyl” further includes alkynyl groups havingoxygen, nitrogen, sulfur or phosphorous atoms replacing one or morehydrocarbon backbone carbons. In certain embodiments, a straight chainor branched chain alkynyl group has six or fewer carbon atoms in itsbackbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Theterm “C₂-C₆” includes alkynyl groups containing two to six carbon atoms.

[0044] The term “alkynyl” also includes both “unsubstituted alkynyls”and “substituted alkynyls”, the latter of which refers to alkynylmoieties having substituents replacing a hydrogen on one or morehydrocarbon backbone carbon atoms. Such substituents can include, forexample, alkyl groups, alkynyl groups, halogens, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0045] Unless the number of carbons is otherwise specified, “loweralkyl” includes an alkyl group, as defined above, but having from one toten, more preferably from one to six, carbon atoms in its backbonestructure. “Lower alkenyl” and “lower alkynyl” have chain lengths of,for example, 2-5 carbon atoms. “Acyl” includes compounds and moietieswhich contain the acyl radical (CH₃CO—) or a carbonyl group.“Substituted acyl” includes acyl groups where one or more of thehydrogen atoms are replaced by for example, alkyl groups, alkynylgroups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

[0046] “Acylamino” includes moieties wherein an acyl moiety is bonded toan amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

[0047] “Aroyl” includes compounds and moieties with an aryl orheteroaromatic moiety bound to a carbonyl group. Examples of aroylgroups include phenylcarboxy, naphthyl carboxy, etc.

[0048] “Alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” includealkyl groups, as described above, which further include oxygen, nitrogenor sulfur atoms replacing one or more hydrocarbon backbone carbon atoms,e.g., oxygen, nitrogen or sulfur atoms.

[0049] The term “alkoxy” includes substituted and unsubstituted alkyl,alkenyl, and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy,propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxygroups include halogenated alkoxy groups. The alkoxy groups can besubstituted with groups such as alkenyl, alkynyl, halogen, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.Examples of halogen substituted alkoxy groups include, but are notlimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0050] The terms “heterocyclyl” or “heterocyclic group” include closedring structures, e.g., 3- to 10-, or 4- to 7-membered rings, whichinclude one or more heteroatoms. Heterocyclyl groups can be saturated orunsaturated and include pyrrolidine, oxolane, thiolane, piperidine,piperizine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringcan be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic orheteroaromatic moiety.

[0051] The term “thiocarbonyl” or “thiocarboxy” includes compounds andmoieties which contain a carbon connected with a double bond to a sulfuratom.

[0052] The term “ether” includes compounds or moieties which contain anoxygen bonded to two different carbon atoms or heteroatoms. For example,the term includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom which is covalentlybonded to another alkyl group.

[0053] The term “ester” includes compounds and moieties which contain acarbon or a heteroatom bound to an oxygen atom which is bonded to thecarbon of a carbonyl group. The term “ester” includes alkoxycarboxygroups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynylgroups are as defined above.

[0054] The term “thioether” includes compounds and moieties whichcontain a sulfur atom bonded to two different carbon or heteroatoms.Examples of thioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom which is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and “alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

[0055] The term “hydroxy” or “hydroxyl” includes groups with an —OH or—O.

[0056] The term “halogen” includes fluorine, bromine, chlorine, iodine,etc. The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

[0057] “Polycyclyl” or “polycyclic radical” refers to two or more cyclicrings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings. Rings that are joined through non-adjacent atoms are termed“bridged” rings. Each of the rings of the polycycle can be substitutedwith such substituents as described above, as for example, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkylamino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or anaromatic or heteroaromatic moiety.

[0058] “Heteroatom” includes atoms of any element other than carbon orhydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur andphosphorus.

[0059] It will be noted that the structure of some of the compounds ofthe invention includes asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of theinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof. Alkenes can include either the E- or Z-geometry,where appropriate.

[0060] Combination therapy” (or “co-therapy”) includes theadministration of a 5-HT modulator of the invention and at least asecond agent as part of a specific treatment regimen intended to providethe beneficial effect from the co-action of these therapeutic agents.The beneficial effect of the combination includes, but is not limitedto, pharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents. Administration of these therapeuticagents in combination typically is carried out over a defined timeperiod (usually minutes, hours, days or weeks depending upon thecombination selected). “Combination therapy” may, but generally is not,intended to encompass the administration of two or more of thesetherapeutic agents as part of separate monotherapy regimens thatincidentally and arbitrarily result in the combinations of the presentinvention. “Combination therapy” is intended to embrace administrationof these therapeutic agents in a sequential manner, that is, whereineach therapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.Substantially simultaneous administration can be accomplished, forexample, by administering to the subject a single capsule having a fixedratio of each therapeutic agent or in multiple, single capsules for eachof the therapeutic agents. Sequential or substantially simultaneousadministration of each therapeutic agent can be effected by anyappropriate route including, but not limited to, oral routes,intravenous routes, intramuscular routes, and direct absorption throughmucous membrane tissues. The therapeutic agents can be administered bythe same route or by different routes. For example, a first therapeuticagent of the combination selected may be administered by intravenousinjection while the other therapeutic agents of the combination may beadministered orally. Alternatively, for example, all therapeutic agentsmay be administered orally or all therapeutic agents may be administeredby intravenous injection. The sequence in which the therapeutic agentsare administered is not narrowly critical. “Combination therapy” alsocan embrace the administration of the therapeutic agents as describedabove in further combination with other biologically active ingredientsand non-drug therapies (e.g., surgery or radiation treatment.) Where thecombination therapy further comprises a non-drug treatment, the non-drugtreatment may be conducted at any suitable time so long as a beneficialeffect from the co-action of the combination of the therapeutic agentsand non-drug treatment is achieved. For example, in appropriate cases,the beneficial effect is still achieved when the non-drug treatment istemporally removed from the administration of the therapeutic agents,perhaps by days or even weeks.

[0061] An “anionic group,” as used herein, refers to a group that isnegatively charged at physiological pH. Preferred anionic groups includecarboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl,phosphate, phosphonate, phosphinate, or phosphorothioate or functionalequivalents thereof. “Functional equivalents” of anionic groups areintended to include bioisosteres, e.g., bioisosteres of a carboxylategroup. Bioisosteres encompass both classical bioisosteric equivalentsand non-classical bioisosteric equivalents. Classical and non-classicalbioisosteres are known in the art (see, e.g., Silverman, R. B. TheOrganic Chemistry of Drug Design and Drug Action, Academic Press, Inc.:San Diego, Calif., 1992, pp.19-23). A particularly preferred anionicgroup is a carboxylate.

[0062] The term “heterocyclic group” is intended to include closed ringstructures in which one or more of the atoms in the ring is an elementother than carbon, for example, nitrogen, or oxygen or sulfur.Heterocyclic groups can be saturated or unsaturated and heterocyclicgroups such as pyrrole and furan can have aromatic character. Theyinclude fused ring structures such as quinoline and isoquinoline. Otherexamples of heterocyclic groups include pyridine and purine.Heterocyclic groups can also be substituted at one or more constituentatoms with, for example, a halogen, a lower alkyl, a lower alkenyl, alower alkoxy, a lower alkylthio, a lower alkylamino, a loweralkylcarboxyl, a nitro, a hydroxyl, —CF₃, —CN, or the like.

[0063] The present invention relates to the discovery of new compoundswhich are 5-HT modulators, e.g., antagonists, and/or SSRIs, that can beused for treating, preventing or curing 5-HT-related conditions. Inparticular, it has been found that certainpiperidinylamino-thieno[2,3-d]pyrimidine compounds are effective 5-HTreceptor modulators and/or SSRIs. In an embodiment, such compoundsinclude those having the formula

[0064] wherein

[0065] R₁ and R₂ may independently be hydrogen; lower alkyl, e.g.,straight or branched C₁, C₂, C₃, C₄ or C₅ alkyl; C₁-C₆ cycloalkyl orcycloheteroalkyl; halogens including F, Cl, Br, I, halo-substitutedalkyls such as CF₃, CF₂CF₃, CH₂CF₃; or R₁ and R₂, taken together, form aC₅-C₇ cycloalkyl, e.g., cyclohexyl, or cycloheteroalkyl ring; Cy may bea single or conjugated substituted or unsubstituted alicyclic, e.g.,cycloalkyl, or, desirably, an aromatic ring structure, e.g., phenyl,naphthyl, diphenylmethyl; and n may be 0, 1, 2, 3, 4 or 5; andpharmaceutically acceptable salts and/or esters thereof.

[0066] In an embodiment, R₁ may desirably be H or —CH₃. In anembodiment, R₂ may desirably be lower alkyl, e.g., straight or branchedC₁, C₂, C₃ (e.g., iso- or tert-butyl), C₄ or C₅ alkyl. R₁ and R₂ mayalso, taken together, desirably form a cyclohexyl ring. The linkinggroup denoted by ( )_(n) may be straight or branched.

[0067] Substituents on Cy include mono-, di-, or tri-substituted phenyl,naphthyl, or biphenyl with lower alkyl, e.g., methyl, ethyl, propyl,allyl, n-butyl, n-pentyl, n-hexyl; alkoxy or aryloxy, e.g., methoxy,ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy,cyclopentyloxy; halo, e.g., fluoro, chloro, bromo, and iodo; amino,dimethylamino, nitro, cyano, carboxy, carboxy esters, carboxamides,N-alkylcarboxamide, N.N-dialkylcarboxamide, trifluoromethyl,trifluoromethoxy, tetrazolo, sulphonyl, thiomethyl, thioethyl,phenylthio, 2,3-methylenedioxy, and 3,4-methylenedioxy. n may be 0, 1, 2or 3. R₁ and R₂, taken together, may form a C₆ cycloalkyl ring.

[0068] In another embodiment compounds of the invention include thosehaving the formula

[0069] wherein

[0070] R₁ and R₂ may independently be hydrogen; lower alkyl, e.g., C₁-C₅alkyl; C₁-C₆ cycloalkyl or cycloheteroalkyl; halogens including F, Cl,Br, I, halo-substituted alkyls such as CF₃, CF₂CF₃, CH₂CF₃; or R₁ andR₂, taken together, form a C₅-C₇ cycloalkyl or cycloheteroalkyl ring;

[0071] R₃ and R₄ may independently be Ar which in turn may be a singleor conjugated substituted or unsubstituted aromatic ring structure,e.g., phenyl, naphthyl, diphenylmethyl; (C₁-C₆)alkyl, (C₁-C₇)cyclohexyl,

[0072] R₅ may be H, (C₁-C₅)alkyl, (C₁-C₆)cycloalkyl, halogen substitutedalkyl, NH₂, NHMe, NMe₂, NHEt, NH(Et)₂, NH(Pr), N(Pr)₂, and n may be 0,1, 2, 3, 4 or 5; and pharmaceutically acceptable salts and/or estersthereof.

[0073] Compounds of the invention may also be 5-HT receptor antagonists,e.g. 5-HT₂ receptor antagonists including 5-HT_(2A, B or C) receptors,and desirably 5-HT_(2B) receptor antagonists.

[0074] In another embodiment compounds of the invention may also be 5-HTreceptor partial agonists, e.g., 5-HT₂ receptor partial agonistsincluding 5-HT_(2A, B or C) receptors, and desirably 5-HT_(2B) receptorpartial agonists.

[0075] In another embodiment compounds of the invention may also be 5-HTreceptor agonists, e.g., 5-HT₂ receptor agonists including5-HT_(2A, B or C) receptors, and desirably 5-HT_(2B) receptor agonists.

[0076] Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat depression in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.

[0077] Another aspect of the invention is a method for treatingdepression in a mammal such as a human comprising administering atherapeutically effective amount of a compound according to Formula I.Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat diseases of the central nervous system in a mammal sufferingtherefrom, and a pharmaceutically acceptable carrier.

[0078] Another aspect of the invention is a method for treating diseasesof the central nervous system in a mammal such as a human comprisingadministering a therapeutically effective is amount of a compoundaccording to Formula I.

[0079] Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat migraine in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.

[0080] Another aspect of the invention is a method for treating migrainein a mammal such as a human comprising administering a therapeuticallyeffective amount of a compound according to Formula I.

[0081] Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective intreating conditions associated with vascular disorders, e.g., angina,migraine, pulmonary hypertension and systemic hypertension.

[0082] Another aspect of the invention is a method of treatingconditions associated with vascular disorders, e.g., angina, migraine,pulmonary hypertension and systemic hypertension.

[0083] Processes for preparing the compounds and novel intermediates arealso included in the invention.

[0084] The compounds of the invention are valuable for treating a widevariety of clinical conditions which are characterized by serotoninexcess or absence, e.g., serotonergic hypofunction or hyperfunction.Such conditions include schizophrenia and other psychotic disorders, forexample, schizophreniform disorders, schizoaffective disorders,delusional disorders, brief psychotic disorders, shared psychoticdisorders and psychotic disorders with delusions or hallucinations;gastrointestinal disorders like Crohn's disease, eating disorders,neuralgia, and addiction disorders; obsessive compulsive disorders,panic disorders, sexual dysfunctions caused by the central nervoussystem and disturbances in sleep and the absorption of food, alcoholism,pain, memory deficits, unipolar depression, dysthymia, bipolardepression, treatment-resistant depression, depression in the medicallyill, panic disorder, obsessive-compulsive disorder, eating disorders,social phobia, premenstrual dysphoric disorder, mood disorders, such asdepression or more particularly depressive disorders, for example,single episodic or recurrent major depressive disorders and dysthymicdisorders, or bipolar disorders, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder; anxiety disorders, such aspanic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobias, e.g., specific animal phobias,social phobias, stress disorders including post-traumatic stressdisorder and acute stress disorder, and generalized anxiety disorders;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Alzheimer's disease, seniledementia, dementia of the Alzheimer's type, vascular dementia, and otherdementias, for example, due to HIV disease, head trauma, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeldt-Jakobdisease, or due to multiple etiologies; Parkinson's disease and otherextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremor; substance-relateddisorders arising from the use of alcohol, amphetamines (oramphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens,inhalants and aerosol propellants, nicotine, opioids, phenylglycidinederivatives, sedatives, hypnotics, and anxiolytics, whichsubstance-related disorders include dependence and abuse, intoxication,withdrawal, intoxication delirium, withdrawal delirium, persistingdementia, psychotic disorders, mood disorders, anxiety disorders, sexualdysfunction and sleep disorders; epilepsy; Down's syndrome;demyelinating diseases such as MS and ALS and other neuropathologicaldisorders such as peripheral neuropathy, for example diabetic andchemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia and other neuralgias; andcerebral vascular disorders due to acute or chronic cerebrovasculardamage such as cerebral infarction, subarachnoid hemorrhage or cerebraledema.

[0085] Compounds of the invention may be used for the treatment of theabove conditions, as well as for vasodilation, smooth musclecontraction, bronchoconstriction, brain disorders such as vasculardisorders, e.g., blood flow disorders caused by vasodilation andvasospastic diseases such as angina, vascular headache, migraine andReynaud's disease; pulmonary hypertension and systemic hypertension; andneuropathological disorders including Parkinson's disease andAlzheimer's disease; modulation of the cardiovascular system;prophylaxis and control of the effects of occurrences of cerebralinfarct (Apoplexia cerebri) such as stroke or cerebral ischemia; and forthe control of disorders of the intestinal tract which are characterizedby disturbances of the serotoninergic system and also by disturbances ofthe carbohydrate metabolism.

[0086] The compounds may also be useful in treating a variety of otherconditions including stress-related somatic disorders; reflexsympathetic dystrophy such as shoulder/hand syndrome; disorders ofbladder function such as cystitis, bladder detrusor hyper-reflexia andincontinence; and pain or nociception attributable to or associated withany of the foregoing conditions, especially pain transmission inmigraine.

[0087] For treating certain conditions it may be desirable to employ thecompounds of the invention in conjunction with another pharmacologicallyactive agent. The compounds of the invention may be presented togetherwith another therapeutic agent as a combined preparation forsimultaneous, separate or sequential use. Such combined preparations maybe, for example, in the form of a twin pack.

[0088] A further aspect of the invention comprises compounds of theinvention in combination with a or another 5-HT antagonist and/or SSRI,e.g., a 5-HT₃ antagonist such as ondansetron, granisetron, tropisetronor zatisetron. Additionally, the compounds of the invention may beadministered in combination with an anti-inflammatory corticosteroid,such as dexamethasone. Furthermore, the compounds of the invention maybe administered in combination with a chemotherapeutic agent such as analkylating agent, anti-metabolite, mitotic inhibitor or cytotoxicantibiotic, as described above. In general, the currently availabledosage forms of the known therapeutic agents for use in suchcombinations will be suitable.

[0089] According to a further or alternative aspect, the inventionprovides compounds of the invention for use in the manufacture of amedicament for the treatment or prevention of physiological disordersassociated with serotonin excess or absence, e.g., serotonergichypofunction or hyperfunction.

[0090] The invention also provides methods for treating or preventingphysiological disorders associated with serotonin excess or absence,e.g., serotonergic hypofunction or hyperfunction, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of the invention or a composition comprising a compound of theinvention.

[0091] For treating or preventing migraine, the compounds of theinvention may be used in conjunction with other anti-migraine agents,such as ergotamines or 5-HT, agonists, especially sumatriptan orrizatriptan. Likewise, for treating behavioral hyperalgesia, thecompounds of the invention may be used in conjunction with an antagonistof N-methyl D-aspartate (NMDA), such as dizocilpine.

[0092] It will be further appreciated that for treating or preventingdepression and/or anxiety, the compounds of the invention may be used incombination with an antidepressant agent or anti-anxiety agent. Suitableclasses of antidepressant agents of use in the invention include:norepinephrine reuptake inhibitors, selective serotonin reuptakeinhibitors, monoamine oxidase inhibitors, reversible monoamine oxidaseinhibitors, serotonin and noradrenaline reuptake inhibitors,corticotropin releasing factor (CRF) antagonists, β-adrenoreceptorantagonists and atypical antidepressants. Another class ofantidepressant agent of use in the invention is noradrenergic andspecific serotonergic antidepressants, such as mirtazapine. Suitableexamples of norepinephrine reuptake inhibitors include amitripdyline,clomipramine, doxepine, imipramine, trimipramine, amoxapine,desipramine, maprotiline, nortriptyline, reboxetine and protriptylineand pharmaceutically acceptable salts thereof. Suitable examples ofselective serotonin reuptake inhibitors include fluoxetine, fluvoxamine,paroxetine, and sertraline and pharmaceutically acceptable saltsthereof. Suitable examples of monoamine oxidase inhibitors includeisocarboxazid, phenelzine, tranylcypromain and selegiline, andpharmaceutically acceptable salts thereof. Suitable examples ofreversible monoamine oxidase inhibitors include moclobemide, andpharmaceutically acceptable salts thereof. Suitable examples ofserotonin and noradrenaline reuptake inhibitors include venlafaxine, andpharmaceutically acceptable salts thereof. Suitable examples ofcorticotropin releasing factor (CRF) antagonists include those compoundsdescribed in International Patent Specification Nos. WO 94/13643, WO94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Suitable examples ofa typical antidepressants include bupropion, lithium, nefazoedone,sibutramine, trazodone and viloxazine, and pharmaceutically acceptablesalts thereof. Other antidepressants of use in the invention includeadinozolam, alaproclate, amineptine, amitryptyline/chlordiazepoxidecombination, atipamezole, azamianserin, bazinaprine, fefuraline,bifemelane, binodaline, bipenamol, brofaromine, bupropion, caroxazone,cericlamine, cianopramine, cimoxatone, citalopram, clemeprol,clovoxamine, dasepinil, deanol, demexiptiline, dibenzepin, dothiepin,droxidopa, enefexine, setazolam, etoperidone, femoxetine, fengabine,fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole,levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine,metralindole, mianserin, milnacipran, minaprine, mirtazapine,montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine,orotirelin, oxaflozane, pinazepam, pirindole, pizotyline, ritaserin,rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine,sulpride, teniloxazine, thozalinone, thymoliberin, tianeptine,tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride,viqualine, zimelidine, and zometapine, and pharmaceutically acceptablesalts thereof, and St. John's wort herb, or Hypericum perforatum, orextracts thereof. Preferred antidepressant agents include selectiveserotonin reuptake inhibitors, in particular, fluoxetine, fluvoxamine,paroxetine, and sertraline and pharmaceutically acceptable saltsthereof.

[0093] Suitable classes of anti-anxiety agents of use in the inventioninclude benzodiazepines and 5-HT_(1A) agonists or antagonists,especially 5-HT_(1A) partial agonists, and corticotropin releasingfactor (CRF) antagonists. In addition to benzodiazepines, other suitableclasses of anti-anxiety agents are nonbenzodiazepine sedative-hypnoticdrugs such as zolpidem; mood-stabilizing drugs such as clobazam,gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol andvigabatrin; and barbiturates. Suitable benzodiazepines of use in theinvention include alprazolam, chlordizepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorezepam, oxazepam and prazepam, andpharmaceutically acceptable salts thereof. Suitable examples of5-HT_(1A) agonists or antagonists of use in the invention include, inparticular, the 5-HT_(1A) partial agonists buspirone, flesinoxan,gepirone, ipsapirone and pindolol, and pharmaceutically acceptable saltsthereof. Another class of anti-anxiety agent of use in the invention arecompounds having muscarinic cholinergic activity. Suitable compounds inthis class include m1 muscarinic cholinergic receptor antagonists suchas those compounds described in European Patent Specification Nos. 0 709093, 0 709 094 and 0 773 021 and International Patent Specification No.WO 96/12711. Another class of anti-anxiety agent of use in the inventionare compounds acting on ion channels. Suitable compounds in this classinclude carbamazepine, lamotrigine and valproate, and pharmaceuticallyacceptable salts thereof.

[0094] Therefore, in a further aspect of the invention, a pharmaceuticalcomposition is provided comprising a compound of the invention and anantidepressant or an anti-anxiety agent, together with at least onepharmaceutically acceptable carrier or excipient.

[0095] Suitable antipsychotic agents of use in combination with thecompounds of the invention include phenothiazines, e.g., chlorpromazine,mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazineand trifluoperazine; thioxanthenes, e.g., chlorprothixene orthiothixene; heterocyclic dibenzazepines, e.g. clozapine or olanzapine;butyrophenones, e.g., haloperidol; diphenylbutylpiperidines, e.g.,pimozide; and indolones, e.g., molindolene. Other antipsychotic agentsinclude loxapine, sulpiride and risperidone. It will be appreciated thatthe antipsychotic agents when used in combination with the compounds ofthe invention may be in the form of a pharmaceutically acceptable salt,for example, chlorpromazine hydrochloride, mesoridazine besylate,thioridazine hydrochloride, acetophenazine maleate, fluphenazinehydrochloride, flurphenazine enathate, fluphenazine decanoate,trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidoldecanoate, loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, olanzapine, haloperidol, pimozide andrisperidone are commonly used in a non-salt form.

[0096] Other classes of antipsychotic agent of use in combination withthe compounds of the invention include dopamine receptor antagonists,especially D2, D3 and D4 dopamine receptor antagonists, and muscarinicm1 receptor agonists. An example of a D3 dopamine receptor antagonist isthe compound PNU-99194A. An example of a D4 dopamine receptor antagonistis PNU-101387. An example of a muscarinic m1 receptor agonist isxanomeline.

[0097] Another class of antipsychotic agent of use in combination withthe compounds of the invention is the 5-HT_(2A) receptor antagonists,examples of which include MDL100907 and fananserin. Also of use incombination with the compound of the invention are the serotonindopamine antagonists (SDAs) which are believed to combine 5-HT_(2A) anddopamine receptor antagonist activity, examples of which includeolanzapine and ziperasidone.

[0098] Therefore, in a further aspect of the invention, a pharmaceuticalcomposition is provided comprising a compound of the invention and anantipsychotic agent, together with at least one pharmaceuticallyacceptable carrier or excipient.

[0099] The compounds of the invention and the other pharmacologicallyactive agent may be administered to a patient simultaneously,sequentially or in combination. It will be appreciated that when using acombination of the invention, the compound of the invention and theother pharmacologically active agent may be in the same pharmaceuticallyacceptable carrier and therefore administered simultaneously. They maybe in separate pharmaceutical carriers such as conventional oral dosageforms which are taken simultaneously. The term “combination” furtherrefers to the case where the compounds are provided in separate dosageforms and are administered sequentially.

[0100] The compounds of the invention may be administered to patients(animals and humans) in need of such treatment in dosages that willprovide optimal pharmaceutical efficacy. It will be appreciated that thedose required for use in any particular application will vary frompatient to patient, not only with the particular compound or compositionselected, but also with the route of administration, the nature of thecondition being treated, the age and condition of the patient,concurrent medication or special diets then being followed by thepatient, and other factors which those skilled in the art willrecognize, with the appropriate dosage ultimately being at thediscretion of the attendant physician.

[0101] In the treatment of a condition associated with a serotoninexcess or absence, e.g., serotonergic hypofunction or hyperfunction, anappropriate dosage level will generally be about 0.001 to 50 mg per kgpatient body weight per day, which may be administered in single ormultiple doses. Preferably, the dosage level will be about 0.01 to about25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.For example, in the treatment or prevention of a disorder of the centralnervous system, a suitable dosage level is about 0.001 to 10 mg/kg perday, preferably about 0.005 to 5 mg/kg per day, and especially about0.01 to 1 mg/kg per day. The compounds may be administered on a regimenof 1 to 4 times per day, preferably once or twice per day.

[0102] It will be appreciated that the amount of the compound of theinvention required for use in any treatment will vary not only with theparticular compounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

[0103] The compositions and combination therapies of the invention maybe administered in combination with a variety of pharmaceuticalexcipients, including stabilizing agents, carriers and/or encapsulationformulations as described herein.

[0104] Aqueous compositions of the present invention comprise aneffective amount of the peptides of the invention, dissolved ordispersed in a pharmaceutically acceptable carrier or aqueous medium.

[0105] “Pharmaceutically or pharmacologically acceptable” includemolecular entities and compositions that do not produce an adverse,allergic or other untoward reaction when administered to an animal, or ahuman, as appropriate. “Pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutical active substances iswell known in the art. Except insofar as any conventional media or agentis incompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

[0106] For human administration, preparations should meet sterility,pyrogenicity, general safety and purity standards as required by FDAOffice of Biologics standards.

[0107] The compositions and combination therapies of the invention willthen generally be formulated for parenteral administration, e.g.,formulated for injection via the intravenous, intramuscular,subcutaneous, intralesional, or even intraperitoneal routes. Thepreparation of an aqueous composition that contains a composition of theinvention or an active component or ingredient will be known to those ofskill in the art in light of the present disclosure. Typically, suchcompositions can be prepared as injectables, either as liquid solutionsor suspensions; solid forms suitable for using to prepare solutions orsuspensions upon the addition of a liquid prior to injection can also beprepared; and the preparations can also be emulsified.

[0108] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions; formulations including sesameoil, peanut oil or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms, such as bacteria and fungi.

[0109] Solutions of active compounds as free base or pharmacologicallyacceptable salts can be prepared in water suitably mixed with asurfactant, such as hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofand in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

[0110] Therapeutic or pharmacological compositions of the presentinvention will generally comprise an effective amount of thecomponent(s) of the combination therapy, dissolved or dispersed in apharmaceutically acceptable medium. Pharmaceutically acceptable media orcarriers include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents for pharmaceuticalactive substances is well known in the art. Supplementary activeingredients can also be incorporated into the therapeutic compositionsof the present invention.

[0111] The preparation of pharmaceutical or pharmacological compositionswill be known to those of skill in the art in light of the presentdisclosure. Typically, such compositions may be prepared as injectables,either as liquid solutions or suspensions; solid forms suitable forsolution in, or suspension in, liquid prior to injection; as tablets orother solids for oral administration; as time release capsules; or inany other form currently used, including cremes, lotions, mouthwashes,inhalants and the like.

[0112] Sterile injectable solutions are prepared by incorporating theactive compounds in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

[0113] The preparation of more, or highly, concentrated solutions forintramuscular injection is also contemplated. In this regard, the use ofDMSO as solvent is preferred as this will result in extremely rapidpenetration, delivering high concentrations of the active compound(s) oragent(s) to a small area.

[0114] The use of sterile formulations, such as saline-based washes, bysurgeons, physicians or health care workers to cleanse a particular areain the operating field may also be particularly useful. Therapeuticformulations in accordance with the present invention may also bereconstituted in the form of mouthwashes, or in conjunction withantifungal reagents. Inhalant forms are also envisioned. The therapeuticformulations of the invention may also be prepared in forms suitable fortopical administration, such as in cremes and lotions.

[0115] Suitable preservatives for use in such a solution includebenzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosaland the like. Suitable buffers include boric acid, sodium and potassiumbicarbonate, sodium and potassium borates, sodium and potassiumcarbonate, sodium acetate, sodium biphosphate and the like, in amountssufficient to maintain the pH at between about pH 6 and pH 8, andpreferably, between about pH 7 and pH 7.5. Suitable tonicity agents aredextran 40, dextran 70, dextrose, glycerin, potassium chloride,propylene glycol, sodium chloride, and the like, such that the sodiumchloride equivalent of the ophthalmic solution is in the range 0.9 plusor minus 0.2%. Suitable antioxidants and stabilizers include sodiumbisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and thelike. Suitable wetting and clarifying agents include polysorbate 80,polysorbate 20, poloxamer 282 and tyloxapol. Suitableviscosity-increasing agents include dextran 40, dextran 70, gelatin,glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin,methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol,polyvinylpyrrolidone, carboxymethylcellulose and the like.

[0116] Upon formulation, therapeutics will be administered in a mannercompatible with the dosage formulation, and in such amount as ispharmacologically effective. The formulations are easily administered ina variety of dosage forms, such as the type of injectable solutionsdescribed above, but drug release capsules and the like can also beemployed.

[0117] In this context, the quantity of active ingredient and volume ofcomposition to be administered depends on the host animal to be treated.Precise amounts of active compound required for administration depend onthe judgment of the practitioner and are peculiar to each individual.

[0118] A minimal volume of a composition required to disperse the activecompounds is typically utilized. Suitable regimes for administration arealso variable, but would be typified by initially administering thecompound and monitoring the results and then giving further controlleddoses at further intervals. For example, for parenteral administration,a suitably buffered, and if necessary, isotonic aqueous solution wouldbe prepared and used for intravenous, intramuscular, subcutaneous oreven intraperitoneal administration. One dosage could be dissolved in 1ml of isotonic NaCl solution and either added to 1000 ml ofhypodermolysis fluid or injected at the proposed site of infusion, (seefor example, Remington's Pharmaceutical Sciences 15th Edition, pages1035-1038 and 1570-1580).

[0119] In certain embodiments, active compounds may be administeredorally. This is contemplated for agents which are generally resistant,or have been rendered resistant, to proteolysis by digestive enzymes.Such compounds are contemplated to include chemically designed ormodified agents; dextrorotatory peptides; and peptide and liposomalformulations in time release capsules to avoid peptidase and lipasedegradation.

[0120] Pharmaceutically acceptable salts include acid addition salts andwhich are formed with inorganic acids such as, for example, hydrochloricor phosphoric acids, or such organic acids as acetic, oxalic, tartaric,mandelic, and the like. Salts formed with the free carboxyl groups canalso be derived from inorganic bases such as, for example, sodium,potassium, ammonium, calcium, or ferric hydroxides, and such organicbases as isopropylamine, trimethylamine, histidine, procaine and thelike.

[0121] The carrier can also be a solvent or dispersion mediumcontaining, for example, water, ethanol, polyol (for example, glycerol,propylene glycol, and liquid polyethylene glycol, and the like),suitable mixtures thereof, and vegetable oils. The proper fluidity canbe maintained, for example, by the use of a coating, such as lecithin,by the maintenance of the required particle size in the case ofdispersion and by the use of surfactants. The prevention of the actionof microorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars or sodium chloride.Prolonged absorption of the injectable compositions can be brought aboutby the use in the compositions of agents delaying absorption, forexample, aluminum monostearate and gelatin.

[0122] Sterile injectable solutions are prepared by incorporating theactive compounds in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

[0123] The preparation of more, or highly, concentrated solutions fordirect injection is also contemplated, where the use of DMSO as solventis envisioned to result in extremely rapid penetration, delivering highconcentrations of the active agents to a small area.

[0124] Upon formulation, solutions will be administered in a mannercompatible with the dosage formulation and in such amount as istherapeutically effective. The formulations are easily administered in avariety of dosage forms, such as the type of injectable solutionsdescribed above, but drug release capsules and the like can also beemployed.

[0125] For parenteral administration in an aqueous solution, forexample, the solution should be suitably buffered if necessary and theliquid diluent first rendered isotonic with sufficient saline orglucose. These particular aqueous solutions are especially suitable forintravenous, intramuscular, subcutaneous and intraperitonealadministration. In this connection, sterile aqueous media which can beemployed will be known to those of skill in the art in light of thepresent disclosure.

[0126] In addition to the compounds formulated for parenteraladministration, such as intravenous or intramuscular injection, otherpharmaceutically acceptable forms include, e.g., tablets or other solidsfor oral administration; liposomal formulations; time-release capsules;and any other form currently used, including cremes.

[0127] Additional formulations suitable for other modes ofadministration include suppositories. For suppositories, traditionalbinders and carriers may include, for example, polyalkylene glycols ortriglycerides; such suppositories may be formed from mixtures containingthe active ingredient in the range of 0.5% to 10%, preferably 1%-2%.

[0128] Oral formulations include such normally employed excipients as,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonateand the like. These compositions take the form of solutions,suspensions, tablets, pills, capsules, sustained release formulations orpowders.

[0129] In certain defined embodiments, oral pharmaceutical compositionswill comprise an inert diluent or assimilable edible carrier, or theymay be enclosed in hard or soft shell gelatin capsule, or they may becompressed into tablets, or they may be incorporated directly with thefood of the diet. For oral therapeutic administration, the activecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tables, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 75% of theweight of the unit, or preferably between 25-60%. The amount of activecompounds in such therapeutically useful compositions is such that asuitable dosage will be obtained.

[0130] The tablets, troches, pills, capsules and the like may alsocontain the following: a binder, as gum tragacanth, acacia, cornstarch,or gelatin; excipients, such as dicalcium phosphate; a disintegratingagent, such as corn starch, potato starch, alginic acid and the like; alubricant, such as magnesium stearate; and a sweetening agent, such assucrose, lactose or saccharin may be added or a flavoring agent, such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup of elixir may contain the active compoundssucrose as a sweetening agent methyl and propylparabensas preservatives,a dye and flavoring, such as cherry or orange flavor.

[0131] The pharmaceutical compositions of this invention may be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains one or more of the compound ofthe invention, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The carriers which canbe used are water, glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate, talc, corn starch, keratin,colloidal silica, potato starch, urea and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition auxiliary, stabilizing, thickening and coloring agentsand perfumes may be used. The active object compound is included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

[0132] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical carrier, e.g.,conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of theinvention. The tablets or pills of the novel composition can be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For example, the tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with such materials asshellac, cetyl alcohol and cellulose acetate.

[0133] The liquid forms in which the compositions of the invention maybe incorporated for administration orally or by injection includeaqueous solution, suitably flavored syrups, aqueous or oil suspensions,and emulsions with acceptable oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, or with a solubilizing or emulsifying agentsuitable for intravenous use, as well as elixirs and similarpharmaceutical vehicles. Suitable dispersing or suspending agents foraqueous suspensions include synthetic and natural gums such astragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

[0134] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulizedby use of inert gases. Nebulized solutions may be breathed directly fromthe nebulizing device or the nebulizing device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

[0135] For treating clinical conditions and diseases noted above, thecompound of this is invention may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

[0136] Methods for preparing the compounds of this invention areillustrated in the following Example(s). The following examples aregiven for the purpose of illustrating the invention, but not forlimiting the scope or spirit of the invention.

[0137] Preparation 1:

[0138] A mixture of 2-Amino-5-alkyl-4-Aryl-thiophene-3-carboxylic acidethyl ester 2 (1 mmol) and ammonium formate (1.5 mmol) in formamide (4mL) was heated at reflux for 12 h. During this time completion ofreaction was monitored via TLC. The reaction mixture was allowed to coolto room temperature and then poured into ice (50 g) to afford a creamyprecipitate. The precipitate was collected by filtration, andrecrystallized from acetone/water to give 3 in typical yields of 70-90%.

[0139] Preparation 2:

[0140] A mixture of 5-Aryl-6-alkyl-thieno[2,3-d]pyrimidin-4-ol (3.7mmol) 3, thionyl chloride (5.5 mL) and dry DMF (0.5 mL) was heated atreflux for 4 h. The reaction mixture was cooled and the excess thionylchloride was removed by vacuum distillation. To the resulting residuewas added 200 g of ice and extracted with dichloromethane (3×100 mL).The combined organic layer was dried (Na₂SO₄) and concentrated. Theproduct was purified by column chromatography (100% DCM) to afford4-Chloro-5-Aryl-6-alkyl-thieno[2,3-d]-pyrimidine 4 in 80-95% yields.

[0141] Preparation 3:

[0142] To a mixture of 4-Boc-amino piperidine 5 (10 mmol) and aromaticaldehyde 6 (10 mmol) in 40 mL of DCM or DCE (1,2-dichloroethane)) underN₂ atmosphere was added sodium triacetoxy borohydride (15 mmol) followedby acetic acid (20 mmol) at room temperature. The resulting cloudymixture was stirred at room temperature for 16 h whereby all thestarting material gets consumed. The reaction mixture was quenched byadding aq.NaHCO₃, and the product was extracted with EtOAC. The organicextract was dried (Na₂SO₄), and the solvent was evaporated to giveproduct 8 in 90-95% yields.

[0143] Preparation 4:

[0144] To a mixture of 4-Boc-amino piperidine 5 (10 mmol) anddiisopropylethylamine (30 mmol) in 30 mL of CH₃CN under N₂ atmospherewas added intermediate 7 (10 mmol) at room temperature. The resultingmixture was refluxed for 16 h. The reaction mixture was quenched byadding aq.NaHCO₃, and the product was extracted with EtOAC. The organicextract was dried (Na₂SO₄), and the solvent was evaporated to giveproduct 8 in 80-94% yields.

[0145] Preparation 5:

[0146] The Boc-protection of crude 4-Boc-aminobenzyl product 8 wasremoved by either treating with 25% TFA-DCM at room temperature for 2 hor with 2M HCl in Et₂O solution at room temperature for 16-20 h. In bothcases, the solvent was evaporated followed by addition of dry Et₂O. Theresulting precipitate was filtered, washed several times with dry Et₂Oand dried under vacuum to afford the corresponding salts of4-amino-1-benzyl piperidine 9. The free base was either isolated orgenerated in situ during the next coupling step.

[0147] Preparation 6:

[0148] To a solution of 4-amino-piperidines 5 (1 mmol) in acetonitrile(5 mL) under N₂ was added diisopropyl ethylamine (4 mmol) followed bychloro-thienopyrimidine 4 (1 mmol). The resulting solution was heated atreflux for 24-48 h (monitored by TLC). The solvent was evaporated and tothe resulting residue was added EtOAc (20 mL). It was washed withaq.NaHCO₃ (10 mL) and brine solution (10 mL). The organic layer wasdried (Na₂SO₄), concentrated and purified by flash column chromatographyon silica gel (1% MeOH in DCM) to afford 11 in 55-60% yields.

[0149] Preparation 7:

[0150] To a solution of 10 (1 mmol) in dry DCM (1 mL) was added 2M HClin ether (10 mL) at 0° C. and stirred the mixture at the sametemperature for 1 h. The precipitated product was filtered and washedwith dry Et₂O and dried in vacuum to afford pure compounds 1 in 90-94%yields.

[0151] Preparation 8:

[0152] To a solution of 10 (1 m. mol) in dry EtOH (2 mL) was addedmaleic acid (1 m.mol) in EtOH (5 mL) at room temperature and stirred themixture for 1 h. the reaction mixture was diluted with ether (5 mL) andcooled at 0° C. for 6-8 h The precipitated product was filtered andwashed with dry Et₂O and dried in vacuum to afford pure compounds 1b in70-95% yields.

[0153] Preparation 9:

[0154] To a solution of 1-Boc-4-amino-piperidine 12 (2 mmol) inacetonitrile (5 mL) under N₂ was added diisopropyl ethylamine (4 mmol)and stirred the mixture for 5 min at room temperature.Chloro-thienopyrimidine 4 was added to the mixture and the contents wereheated at reflux for 16 h (monitored by TLC). The solvent was evaporatedand to the residue was added EtOAc (20 mL) and water (10 mL). Theorganic layer was dried (MgSO₄), and concentrated to yield crudeproduct. Flash column chromatography on silica gel (1% MeOH in DCM)afforded the pure products 13 in 80-85% yields.

[0155] Preparation 10:

[0156] The Boc-protection of 13 was removed by either treating with 25%TFA-DCM at room temperature for 2 h or with 2M HCl in Et₂O solution atroom temperature for 16-20 h. In both cases, the solvent was evaporatedfollowed by addition of dry Et₂O. The resulting precipitate wasfiltered, washed several times with dry Et₂O and dried under vacuum toafford the salts 14 in 95-97% yields. The corresponding free base waseither isolated or generated in situ during the next coupling step.

[0157] Preparation 11:

[0158] To a mixture of 14 (10 mmol) and aldehyde 6 (10 mmol) in 40 mL ofDCM or DCE (1,2-dichloroethane)) under N₂ atmosphere was added sodiumtriacetoxy borohydride (15 mmol) followed by acetic acid (20 mmol) atroom temperature. The resulting cloudy mixture was stirred at roomtemperature for 16 h whereby all the starting material gets consumed.The reaction mixture was quenched by adding aq.NaHCO₃, and the productwas extracted with EtOAC. The EtOAC extract was dried (MgSO₄) and thesolvent was evaporated to give the crude product. Purification by flashcolumn on silica gel or crystallization afforded the pure products 11 in90-95% yields.

[0159] Preparation 12:

[0160] To a mixture of 13 (10 mmol) and diisopropylethylamine (30 mmol)in 30 mL of CH₃CN under N₂ atmosphere was added intermediate 7 (10 mmol)at room temperature. The resulting mixture was refluxed for 16 h. Thereaction mixture was quenched by adding aq.NaHCO₃, and the product wasextracted with EtOAC. The organic extract was dried (Na₂SO₄), and thesolvent was evaporated to give product 8 in 80-94% yields.

EXAMPLE 1

[0161]N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine,monomaleate.

[0162] The title compound was prepared (36 mg, 75%) fromN-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine(38 mg, 0.095 mmol) by following the procedure described for Preparation8. ¹H NMR (400 MHz, DMSO-d₆): δ 8.25 (s, 1H), 7.65 (bs, 1H), 7.35 (m,2H), 7.25 (d, 2H), 6.05 (s, 2H), 4.20 (m, 3H), 3.30 (m, 2H), 3.00 (m,2H), 2.10 (m, 2H), 1.80 (m, 2H), 1.30 (d, 6H). MS (ESI) m/z: Calculated:402.5; Observed: 403.2 (M⁺+1).

EXAMPLE 2

[0163]N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine,monomaleate.

[0164] The title compound was obtained in 64% yield following theprocedure described in preparation 8. ¹H NMR (400 MHz, MeOH-d⁴): δ 8.33(s, 1H), 7.46 (s, 1H), 7.18 (m, 3H), 6.23 (s, 2H, maleate), 4.38 (m,1H), 4.30 (s, 2H), 3.51 (m, 2H), 3.16 (m, 2H), 2.31 (m, 2H), 1.93 (m,2H); MS (ESI) m/z: Calculated for C₁₈H₁₈ClF₂N₄S, 395.09; Observed: 395.0(M⁺+1).

EXAMPLE 3

[0165]N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine,dihydrochloride.

[0166] The title compound was prepared (110 mg, 93%) fromN-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine(100 mg, 0.25 mmol) by following the procedure described for Preparation7. ¹H NMR (400 MHz, CD₃OD): δ 8.50 (s,1H), 7.60 (s,1H), 7.30 (m, 2H),7.15 (m, 1H), 4.65 (m, 1H), 4.40 (s, 2H), 3.65 (m, 2H), 3.30 (m, 3H),2.35 (m, 2H), 2.15 (m, 2H), 1.40 (d, 6H). MS (ESI) m/z: Calculated:402.5; Observed: 403.1 (M⁺+1).

EXAMPLE 4

[0167]N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-aminedihydrochloride

[0168] The title compound was obtained in 66% yield following theprocedure described in Preparation 7. ¹H NMR (400 MHz, MeOH-d⁴): δ 8.63(s, 1H), 7.70 (s, 1H), 7.27 (d, 2H), 7.17 (s, 1H), 4.56 (s, 1H), 4.40(s, 2H), 3.62 (d, 2H), 3.29 (d, 2H), 2.35 (d, 2H), 2.05 (m, 2H); MS(ESI) m/z: Calculated for C₁₈H₁₈ClF₂N₄S, 395.09; Observed: 395.0 (M⁺+1).

EXAMPLE 5

[0169]N-(1-(1-(3-fluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-aminedihydrochloride

[0170] The title compound was prepared (66 mg, 73%) fromN-(1-(1-(3-fluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine(77 mg, 0.186 mmol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.65 (s, 1H), 7.40-7.60 (m,5H), 4.55 (m, 2H), 3.95 (d, 1H), 3.40 (d, 1H), 3.20 (m, 1H), 3.10 (m,1H), 2.85 (d, 2H), 2.25-2.45 (m, 3H), 2.15 (m, 1H), 2.00 (m, 1H), 1.85(d, 3H), 1.00 (d, 6H). MS (ESI) m/z: Calculated: 412.57; Observed: 413.1(M⁺+1).

EXAMPLE 6

[0171]N-(1-(1-(3,5-difluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-aminedihydrochloride

[0172] The title compound was prepared (77 mg, 53%) fromN-(1-(1-(3,5-difluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine(125 mg, 0.29 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.65 9s, 1H), 7.55 (s, 1H),7.35 (m, 2H), 7.15 (m, 1H), 4.60 (m, 2H), 3.95 (d, 1H), 3.45 (d, 1H),3.05-3.25 (m, 2H), 2.85 (d, 2H), 2.40 (m, 1H), 2.30 (m, 2H), 2.00 (m,1H), 1.80 (d, 3H), 1.00 (d, 6H). MS (ESI) m/z: Calculated: 430.56;Observed: 431.1 (M⁺+1).

EXAMPLE 7

[0173]4-N-(3-(1-(3-Fluorophenyl)ethylamino)propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine,dihydrochloride.

[0174] The title compound was prepared (186 mg, 54%) from4N-(3-(1-(3-Fluorophenyl)ethylamino)propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine(262 mg, 0.76 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.60 (s, 1H), 7.45 (m, 1H),7.35 (m, 2H), 7.15 (m, 1H), 4.45 9(q, 1H), 3.80 (m, 2H), 2.80-3.10 (m,6H), 2.15 (m, 2H), 1.95 (m, 2H), 1.65 (d, 3H). MS (ESI) m/z: Calculated:384.51; Observed: 385.1 (M⁺+1).

EXAMPLE 8

[0175] 4N-(3-(3-Fluorobenzylamino)propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine,dihydrochloride.

[0176] The title compound was prepared (105 mg, 61%) from4N-(3-(3-Fluorobenzylamino)propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine(145 mg, 0.39 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.65 (s, 1H), 7.50 (m, 1H),7.35 (m, 2H), 7.10 (m, 1H), 4.25 (s, 2H), 3.90 (t, 2H), 3.20 (t, 2H),3.05 (m, 2H), 2.90 (m, 2H), 2.10 (m, 2H), 1.95 (m, 4H). MS (ESI) m/z:Calculated: 370.49; Observed: 371.1 (M⁺+1).

EXAMPLE 9

[0177] N-(3-(1-(3-fluorophenyl)ethylamino)propyl)-6isobutylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0178] The title compound was prepared (142 mg, 76%) fromN-(3-(1-(3-fluorophenyl)ethylamino)propyl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine(157 mg, 0.4 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.60 (s, 1H), 7.45 (m, 2H),7.35 (m, 2H), 7.15 (m, 1H), 4.45 (m, 1H), 3.80 (m, 2H), 3.10 (m, 1H),2.95 (m, 1H), 2.85 (d, 2H), 2.15 (m, 2H), 2.00 (m, 1H), 1.70 (d, 3H),1.00 (d, 6H). MS (ESI) m/z: Calculated: 386.53; Observed: 387.1 (M⁺+1).

EXAMPLE 10

[0179]N-(1-(1-(2,4,6-trifluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin4-amine, dihydrochloride

[0180] The title compound was prepared (90 mg, 71%) fromN-(1-(1-(2,4,6-trifluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine(110 mg, 0.25 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.05 (s, 1H), 7.60 (s, 1H),7.15 9m, 2H), 5.00 (m, 1H), 4.60 (m, 1H), 3.65-3.90 (m, 2H), 3.10-3.35(m, 2H), 2.85 (d, 2H), 2.10-2.45 (m, 4H), 2.00 (m, 1H), 1.90 (d, 3H),1.05 (d, 6H). MS (ESI) m/z: Calculated: 448.55; Observed: 449.1 (M⁺+1).

EXAMPLE 11

[0181]N-(1-(1-(2,6-difluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine,dihydrochloride

[0182] The title compound was prepared (105 mg, 87%) fromN-(1-(1-(2,6-difluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine(104 mg, 0.24 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.65 (s, 1H), 7.65 (m, 1H),7.60 (s, 1H), 7.20 (t, 2H), 5.00 (m, 1H), 4.60 (m, 1H), 3.90 (d, 1H),3.70 (d, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.85 (d, 2H), 2.10-2.45 (m,4H), 2.00 (m, 1H), 1.90 (d, 3H), 1.00 (d, 6H). MS (ESI) m/z: Calculated:430.56; Observed: 431.2 (m⁺+1).

EXAMPLE 12

[0183]N-(1-(cyclohexylmethyl)piperidin-4-yl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine,dihydrochloride

[0184] The title compound was obtained in 85% yield following theprocedure described in Preparation 7. ¹H NMR (400 MHz, MeOH-d⁴): δ 8.68(s, 1H), 4.70 (m, 1H), 3.71 (d, 2H), 3.20 (m, 2H), 3.01 (d, 2H), 2.61(s, 3H), 2.53 (s, 3H), 2.40-2.20 (m, 4H), 1.88-1.71 (m, 6H), 1.39-1.26(m, 3H), 1.09 (m, 2H); MS (ESI) m/z: Calculated for C₂₀H₃₁N₄S, 359.23;Observed: 359.2 (M⁺+1).

EXAMPLE 13

[0185]N-(1-(3-fluorobenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-4-amine,dihydrochloride.

[0186] The title compound was prepared (98 mg, 70%) fromN-(1-(3-fluorobenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-4-amine(119 mg, 0.3 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.05 (s, 1H), 7.55 (m, 1H),7.40 (m, 2H), 7.25 (m, 1H), 4.65 (m, 1H), 4.40 (s, 2H), 3.65 (m, 2H),3.25 (m, 2H), 2.65 (s, 3H), 2.35 (m, 2H), 2.15 (m, 2H). MS (ESI) m/z:Calculated: 390.91; Observed: 391.2 (M⁺+1).

EXAMPLE 14

[0187]2-((4-(6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzonitrile,dihydrochloride

[0188] The title compound was prepared (94 mg, 80%) from2-((4-(6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzonitrile(100 mg, 0.25 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.70 (s, 1H), 7.95 (m, 2H),7.85 (t, 1H), 7.75 (t, 1H), 4.70 (m, 1H), 4.60 (s, 2H), 3.70 (d, 2H),3.45 (m, 2H), 2.65 (s, 3H), 2.15-2.45 (m, 4H). MS (ESI) m/z: Calculated:397.92; Observed: 398.1 (M⁺+1).

EXAMPLE 15

[0189]N-(1-(2-methoxybenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin4-amine, dihydrochloride

[0190] The title compound was prepared (129 mg, 95%) fromN-(1-(2-methoxybenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-4-amine(115 mg, 0.29 m. mol) by following the general procedure described forPreparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.90 (s, 1H), 7.50 (m, 2H),7.15 (m, 1H), 7.05 (t, 1H), 4.65 (m, 1H), 4.40 (s, 2H), 3.95 (s, 3H),3.65 (m, 2H), 3.30 (m, 2H), 2.65 (s, 3H), 2.35 (m, 2H), 2.20 (m, 2H). MS(ESI) m/z: Calculated: 402.94; Observed: 403.3 (M⁺+1).

EXAMPLE 16

[0191]N-(1-(3-fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine,dihydrochloride

[0192] The title compound was obtained in 90% yield following theprocedure described in Preparation 7. ¹H NMR (400 MHz, MeOH-d⁴): δ 8.63(s, 1H), 7.70 (s, 1H), 7.55 (dt, 1H), 7.39 (m, 2H), 7.28 (t, 2H), 4.56(m, 1H), 4.39 (s, 2H), 3.62 (d, 2H), 3.29 (d, 2H), 2.35 (d, 2H), 2.04(m, 2H); MS (ESI) m/z: Calculated for C₁₈H₁₉ClFN₄S, 377.1; Observed:377.2 (M⁺+1).

EXAMPLE 17

[0193][1-(3-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0194] The title compound was prepared in 91% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.75(s, 1H), 7.58-7.49 (m, 1H), 7.48-7.40 (m, 2H), 7.60 (t, 1H), 4.70 (m,1H), 4.39 (s, 2H), 3.61 (m, 2H), 3.30 (t, 2H), 3.24-3.12 (m, 2H),2.99-2.81 (m, 2H), 2.41-2.29 (m, 4H), 2.02-1.91 (m, 4H). MS (ESI) m/z:Calculated: 396.5; Observed: 397.5 (M⁺+1).

EXAMPLE 18

[0195](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(3-fluoro-phenylethyl)-piperidin-4-yl]-amine,dihydrochloride

[0196] The title compound was prepared in 91% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.67 (s,1H), 7.57-7.43 (m, 3H), 7.26 (t, 1H), 4.62 (m, 1H), 4.53 (q, 1H),3.18-3.01 (m, 2H), 2.91 (t, 2H), 2.56-2.39 (m, 4H), 1.96-1.95 (m, 4H),1.83 (d, 3H). MS (ESI) m/z: Calculated: 410.5; Observed: 411.2 (M⁺+1).

EXAMPLE 19

[0197]N-{1-[1-(3-fluorophenyl)-ethyl]piperidin-4-yl}-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine,dihydrochloride

[0198] The title compound was prepared in 84% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.66(s, 1H), 7.37-7.22 (m, 1H), 7.17-7.03 (m, 3H), 4.514.37 (m, 1H), 4.20(q, 1H), 3.70-3.56 (m, 4H), 2.64 (s, 3H), 2.62 (s, 3H), 2.54-2.49 (m,2H), 2.02-1.89(m, 2H), 1.82 (d, 3H). MS (ESI) m/z: Calculated: 384.5;Observed: 385.2 (M⁺+1).

EXAMPLE 20

[0199](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(3,5-difluoro-phenylethyl)-piperidin-4-yl]-amine, dihydrochloride

[0200] The title compound was prepared in 89% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.61 (s,1H), 7.34 (m, 2H), 7.16 (m, 1H), 4.83 (bs, 3H), 4.63 (m, 1H), 4.56 (m,1H), 3.91 (m, 1H), 3.51-2.87 (m, 4H), 2.39-1.85 (m, 11H), 1.81 (d, 3H).MS (ESI) m/z: Calculated: 428.5; Observed: 429.1 (M⁺+1).

EXAMPLE 21

[0201][1-(2-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0202] The title compound was prepared in 88% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.72(s, 1H), 7.58-7.49 (m, 1H), 7.48-7.40 (m, 2H), 7.60 (t, 1H), 4.70 (m,1H), 4.39 (s, 2H), 3.61 (m, 2H), 3.30 (t, 2H), 3.04-3.12 (m, 2H),2.89-2.91 (m, 2H), 2.21-2.39 (m, 4H), 1.91-2.02 (m, 4H), MS (ESI) m/z:Calculated: 396.5; Observed: 397.5 (M⁺+1).

EXAMPLE 22

[0203][1-(4-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0204] The title compound was prepared in 89% yield in following theprocedure described in Preparation. ¹H NMR (400 MHz, CD₃OD): δ 8.71 (s,1H), 7.54-7.40 (m, 2H), 7.22-7.14 (m, 2H), 4.64 (m, 1H), 4.32 (s, 2H),3.78-3.65 (m, 2H), 3.59-3.41 (m, 4H), 2.95-2.87 (m, 4H), 2.45-2.31 (m,4H), 2.15-2.01 (m, 4H). MS (ESI) m/z: Calculated: 396.5; Observed: 397.5(M⁺+1).

EXAMPLE 23

[0205][1-(3-Cyano-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0206] The title compound was prepared in 91% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.70(s, 1H), 8.02 (s, 1H), 7.96 (d, 1H), 7.90 (d, 1H), 7.70(t, 1H), 4.71 (m,1H), 4.45 (s, 2H), 3.62-3.59 (m, 2H), 3.07 (t, 2H), 2.90 (t, 2H),2.34-2.15 (m, 4H), 1.98-1.92 (m, 6H). MS (ESI) m/z: Calculated: 403.5;Observed: 404.3 (M⁺+1).

EXAMPLE 24

[0207]N-{1-(3-fluorophenyl)-(ethyl)piperedin-4-yl}thieno[2,3-d]pyrimidin-4-amine,dihydrochloride

[0208] The title compound was prepared in 82% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.70 (s,1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.22-7.14 (m, 3H), 4.69-4.50 (m, 1H),4.52 (q, 1H), 3.50-3.37 (m, 4H), 2.39-1.85 (d, 2H), 1.80 (d, 3H). MS(ESI) m/z: Calculated: 356.4; Observed: 357.2 (M⁺+1).

EXAMPLE 25

[0209]N-{1-[2-(3-fluorophenyl)propan-2yl]piperidin-4-yl}(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0210] The title compound was prepared in 91% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.55 (s,1H), 7.43-7.29 (m, 3H), 7.22 (t, 1H), 4.42 (m, 1H), 3.18-3.01 (m, 2H),2.91 (t, 2H), 2.56-2.39 (m, 4H), 1.96-1.95 (m, 4H), 1.46 (s, 3H), 1.44(s, 3H). MS (ESI) m/z: Calculated: 424.5; Observed: 425.1 (M⁺+1).

EXAMPLE 26

[0211]N-{1-(3,5,difluorobenzyl)piperedin-4-yl}thieno[2,3-d]pyrimidin-4-amine,dihydrochloride

[0212] The title compound was prepared in 82% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.70 (s,1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.22-7.14 (m, 3H), 4.66 (m, 1H), 3.91(s, 2H), 3.50-3.37 (m, 4H), 2.39-1.85 (d, 2H). MS (ESI) m/z: Calculated:360.42; Observed: 361.1 (M⁺+1).

EXAMPLE 27

[0213](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(2,4,6-trifluoro-phenyl)(2-methylpropyl)-piperidin-4-yl]-amine,dihydrochloride

[0214] The title compound was prepared in 85% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.69 (s,1H), 7.44-7.31 (m, 1H), 7.20-7.01 (m, 3H), 4.66-4.55 (m, 1H), 4.474.50(m, 1H), 3.30-3.17 (m, 4H), 2.66-2.42 (m, 4H), 2.20-1.87 (m, 9H),1.85-1.70 (m, 2H), 1.22 (d, 3H), 1.20 (d, 2H). MS (ESI) m/z: Calculated:452.6; Observed: 453.2 (M⁺+1).

EXAMPLE 28

[0215][1-(4-Methyl-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0216] The title compound was prepared in 82% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.70(s, 1H), 7.54-7.40 (d, 2H), 7.25-7.12 (d, 2H), 4.76 (m, 1H), 3.99 (s,2H), 3.03-2.89 (m, 4H), 2.50 (s, 3H), 2.29-2.17 (m, 2H), 2.12-2.02 (m,2H), 1.99-1.89 (m, 4H), 1.73-1.50 (m, 4H). MS (ESI) m/z: Calculated:392.56; Observed: 393.6 (M⁺+1).

EXAMPLE 29

[0217][1-(4-Methoxy-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0218] The title compound was prepared in 85% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.77(s, 1H), 7.40-7-32 (d, 2H), 7.01 (d, 2H), 4.60 (m, 1H), 3.91 (s, 3H),3.68 (s, 2H), 2.97-2.86 (m, 2H), 2.80-2.71 (t, 2H), 2.29-2.10 (m, 2H),2.09-2.01 (m, 2H), 1.99-1.91 (m, 4H), 1.72-1.60 (m, 4H). MS (ESI) m/z:Calculated: 408.5; Observed: 409.6 (M⁺+1).

EXAMPLE 30

[0219](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(4-trifluoromethoxy-benzyl)-piperidin-4-yl]-amine,dihydrochloride

[0220] The title compound was prepared in 80% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.80(s, 1H), 7.49-7.36 (m, 4H), 3.99 (s, 2H), 3.12-2.99 (m, 1H), 2.98-2.78(m, 4H), 2.31-2.20 (m, 2H), 2.15-1.98 (m, 2H), 1.90-1.78 (m, 4H),1.76-1.66 (m, 4H). MS (ESI) m/z: Calculated: 462.5; Observed: 463.4(M⁺+1).

EXAMPLE 31

[0221](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(3,4-methylenedioxy-benzyl)-piperidin-4-yl]-amine,dihydrochloride

[0222] The title compound was prepared in 75% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.80(s, 1H), 7.45 (d, 1H), 7.22-7.01 (m, 2H), 6.02 (s, 2H), 4.69 (m, 1H),3.77 (s, 2H), 3.21-3.04 (m, 2H), 2.98 (t, 2H), 2.43-2.22 (m, 2H),2.25-2.01 (m, 2H), 1.99-1.87 (m, 4H), 1.65-1.60 (m, 4H). MS (ESI) m/z:Calculated: 422.5; Observed: 423.3 (M⁺+1).

EXAMPLE 32

[0223]2-{4-(5,6-Dimethylthieno[2,3-d]pyrimidin-4-ylamino)piperedin-1-yl-methyl}benzonitrile,dihydrochloride

[0224] The title compound was prepared in 88% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.72(s, 1H), 7.97-7.90 (m, 1H), 7.77-7.63 (m, 3H), 4.61-4.57 (m, 1H), 3.98(s, 2H), 3.52-3.44 (m, 4H), 2.64 (s, 3H), 2.62 (s, 3H), 2.54-2.49 (m,2H), 2.02-1.89(m, 2H). MS (ESI) m/z: Calculated: 377.5; Observed: 378.1(M⁺+1).

EXAMPLE 33

[0225]5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(2,6-difluorophenyl-ethyl)-piperidin-4-yl]-amine,dihydrochloride

[0226] The title compound was prepared in 87% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.65 (s,1H), 7.67-7.51 (m, 1H), 7.20-7.12 (t, 2H), 4.78 (q, 1H), 4.71-4.63 (m,1H), 3.54 (t, 2H), 3.01 (t, 2H), 2.39-2.21 (m, 4H), 2.09-1.89 (m, 4H),1.84 (d, 3H). MS (ESI) m/z: Calculated: 428.5; Observed: 429.1 (M⁺+1).

EXAMPLE 34

[0227](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(2,4,6-trifluoro-phenylethyl)-piperidin-4-yl]-amine,dihydrochloride

[0228] The title compound was prepared in 90% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.71 (s,1H), 7.22 (t, 2H), 4.66 (q, 1H), 4.69-4.52 (m, 1H), 3.34-3.19 (m, 4H),2.69-2.41 (m, 4H), 2.12-1.99 (m, 8H), 1.80 (d, 3H). MS (ESI) m/z:Calculated: 446 5; Observed: 447.2 (M⁺+1).

EXAMPLE 35

[0229][1-(2,2-Diphenyl-ethyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0230] Pure product was obtained by column chromatography (2% MeOH-DCM)in 46% yield. ¹H NMR (400 MHz, CD₃OD): δ 8.80 (s, 1H), 7.99-7.81 (m,6H), 7.64-7.51 (m, 4H), 4.99 (m, 1H), 3.56 (m, 2H), 3.01-2.92 (m, 1H),2.90-2.74 (m, 4H), 2.33-2.20 (m, 2H), 2.01-1.90 (m, 2H), 1.87-1.80 (m,4H), 1.69-1.52 (m, 4H). MS (ESI) m/z: Calculated: 468.6; Observed: 469.8(M⁺+1).

EXAMPLE 36

[0231](1-Naphthalen-2-ylmethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0232] The title compound was prepared in 77% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.65(s, 1H), 8.22-8.13 (m, 3H), 7.92-7.77 (m, 4H), 4.56 (m, 1H), 3.92 (s,2H), 3.14-3.00 (m, 1H), 2.94-2.82 (m, 4H), 2.20-2.01 (m, 2H), 2.00-1.90(m, 2H), 1.89-1.74 (m, 4H), 1.60-1.49 (m, 4H). MS (ESI) m/z: Calculated:428.5; Observed: 429.8 (M⁺+1).

EXAMPLE 37

[0233][1-(4-Chloro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4]thieno[2,3-d]pyrimidin-4-yl)-amine,dihydrochloride

[0234] The title compound was prepared in 82% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.72(s, 1H), 7.54-7.43 (m, 2H), 7.24-7.11 (m, 2H), 4.64 (m, 1H), 4.32 (s,2H), 3.78-3.65 (m, 2H), 3.59-3.41 (m, 4H), 2.95-2.87 (m, 4H), 2.45-2.31(m, 4H), 2.15-2.01 (m, 4H). MS (ESI) m/z: Calculated: 412.9; Observed:413.7 (M⁺+1).

EXAMPLE 38

[0235](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(3,5-difluoro-phenylethyl)-piperidin-4-yl]-amine,dihydrochloride

[0236] The title compound was prepared in 89% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD):δ 8.61 (s,1H), 7.34 (m, 2H), 7.16 (m, 1H), 4.83 (bs, 3H), 4.63 (m, 1H), 4.56 (m,1H), 3.91 (m, 1H), 3.51-2.87 (m, 4H), 2.39-1.85 (m, 11H), 1.81 (d, 3H).MS (ESI) m/z: Calculated: 428.5; Observed: 429.1 (M⁺+1).

EXAMPLE 39

[0237]N-{1-[1-(3-fluorophenyl)-ethyl]piperidin-4-yl}-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine,dihydrochloride

[0238] The title compound was prepared in 84% yield in following theprocedure described in Preparation 7. ¹H NMR (400 MHz, CD₃OD): δ 8.66(s, 1H), 7.37-7.22 (m, 1H), 7.17-7.03 (m, 3H), 4.51-4.37 (m, 1H), 4.20(q, 1H), 3.70-3.56 (m, 4H), 2.64 (s, 3H), 2.62 (s, 3H), 2.54-2.49 (m,2H), 2.02-1.89(m, 2H), 1.82 (d, 3H). MS (ESI) m/z: Calculated: 384.5;Observed: 385.2 (M⁺+1).

EXAMPLE 40

[0239]N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine

[0240] The title compound was prepared (264 mg, 56%) from4-chloro-6-isopropylthieno[2,3-d]pyrimidine (0.25 g, 1.18 mmol) and1-(3,5-difluorobenzyl)piperidin-4-amine (0.4 g, 1.77 mmol) by followingthe general procedure described for Preparation 6. ¹H NMR (400 MHz,CDCl₃): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.80 (s, 1H), 6.70 (m, 1H), 4.95(d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 3.20 (m, 1H), 2.85 (m, 2H), 2.25(m, 2H), 2.10 (m, 2H), 1.60 (m, 2H), 1.40 (d, 6H). MS (ESI) m/z:Calculated: 402.5; Observed: 403.1 (M⁺+1).

EXAMPLE 41

[0241]N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine

[0242] The title compound was obtained in 44% yield following theprocedure described in preparation 10 followed by preparation 11. ¹H NMR(400 MHz, CDCl₃): δ 8.44 (s, 1H), 6.99 (s, 1H), 6.89 (d, 2H), 6.70 (t,1H), 4.89 (d, 1H), 4.19 (m, 1H), 3.50 (s, 2H), 2.86 (d, 2H), 2.24 (t,2H), 2.01 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated forC₁₈H₁₈ClF₂N₄S, 395.09; Observed: 395.0 (M⁺+1).

EXAMPLE 42

[0243]N-(1-(3-fluorobenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-4-amine

[0244] The title compound was prepared (119 mg, 91%) from6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95mg, 0.336 m. mol) and 1-(bromomethyl)-3-fluorobenzene (70 mg, 0.37 m.mol) by following the general procedure described for Preparation 12. ¹HNMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.10 (m, 2H), 6.95(m, 1H), 5.30 (d, 1H), 4.05 (m, 1H), 3.55 (s, 2H), 2.95 (m, 2H), 2.50(s, 3H), 2.25 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z:Calculated: 390.91; Observed: 391.2 (M⁺+1).

EXAMPLE 43

[0245]2-((4-(6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzonitrile

[0246] The title compound was prepared (100 mg, 75%) from6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95mg, 0.336 m. mol) and 2-(bromomethyl)benzonitrile (73 mg, 0.37 m. mol)by following the general procedure described for Preparation 12. ¹H NMR(400 MHz, CDCl₃): δ 8.40 (s, 1H), 7.65 (d, 1H), 7.55 (m, 2H), 7.35 (m,1H), 5.30 (d, 1H), 4.25 (m, 1H), 3.7 (s, 2H), 2.85 (m, 2H), 2.50 (s,3H), 2.40 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m/z: Calculated:397.92; Observed: 398.2 (M⁺+1).

EXAMPLE 44

[0247]N-(1-(2-methoxybenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-4-amine

[0248] The title compound was prepared (115 mg, 85%) from6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95mg, 0.336 m. mol) and 1-(chloromethyl)-2-methoxybenzene (58 mg, 0.37 m.mol) by following the general procedure described for Preparation 12. ¹HNMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 6.95(m, 1H), 6.85 (d, 1H), 5.35 (d, 1H), 4.25 (m, 1H), 3.85 (s, 3H), 3.60(s, 2H), 2.90 (m, 2H), 2.50 (s, 3H), 2.35 (m, 2H), 2.10 (m, 2H), 1.40(m, 2H). MS (ESI) m/z: Calculated: 402.94; Observed: 403.2 (M⁺+1).

EXAMPLE 45

[0249]N-(1-(3-fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine

[0250] The title compound was obtained in 53% yield following theprocedure described in preparation 10 followed by preparation 12. ¹H NMR(400 MHz, CDCl₃): δ 8.44 (s, 1H), 7.28 (dd, 1H), 7.09 (d, 1H), 7.08 (d,1H), 6.98 (s, 1H), 6.95 (dt, 1H), 4.85 (d, 1H), 4.19 (m, 1H), 3.49 (s,2H), 2.87 (d, 2H), 2.23 (dt, 2H), 2.09 (d, 2H), 1.60 (m, 2H); MS (ESI)m/z: Calculated for C₁₈H₁₉ClFN₄S, 377.1; Observed: 377.2 (M⁺+1).

EXAMPLE 46

[0251]N-(1-(11-(3-fluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine

[0252] The title compound was prepared (291 mg, 64%) from4-chloro-6-isobutylthieno[2,3-d]pyrimidine (250 mg, 1.1 mmol) and1-(1-(3-fluorophenyl)ethyl)piperidin-4-amine (0.49 mg, 2.2 m. mol) byfollowing the general procedure described for Preparation 6. ¹H NMR (400MHz, CDCl₃): δ 8.40 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H),6.75 (s, 1H), 5.00 (m, 1H), 4.10 (m, 1H), 3.45 (m, 1H), 3.00 (d, 1H),2.80 (d, 1H), 2.70 (d, 2H), 1.85-2.25 (m, 5H), 1.45-1.65 (m, 2H), 1.35(d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 412.57; Observed: 413.3(M⁺+1).

EXAMPLE 47

[0253] 4N-(3-(3-Fluorobenzylamino)propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine

[0254] The title compound was prepared (127 mg, 69%) from6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (125 mg,0.43 m. mol) and 1-(3,5-difluorophenyl)ethyl methanesulfonate (243 mg,1.03 mmol) by following the general procedure described for Preparation12. ¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.75 (s, 1H),6.70 (m, 1H), 4.95 (d, 1H), 4.15 (m, 1H), 3.45 (m, 1H), 2.95 (m, 1H),2.80 (m, 1H), 2.70 (d, 2H), 2.20 (m, 4H), 1.95 (m, 1H), 1.55 (m, 2H),1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 430.56; Observed:431.1 (M⁺+1).

EXAMPLE 48

[0255]

[0256] To a mixture of piperidine intermediate 14 (10 mmol) and3-Fluorophenylacetophenone (10 mmol) in dry DCM was added titaniumisopropoxide (10 mmol) at room temperature and stirred for 24 h.Diethylaluminumcyanide (10 mmol) was added to the above solution and themixture was allowed to stir for 24 h. The reaction was quenched by theaddition of saturated aq. NaHCO₃ solution and the organic layer wasseparated, dried and concentrated under reduced pressure to give thecyano derivative 16 as pale yellow powder in quantitative yield. Thecrude compound 16 was dissolved in dry THF and was added MeMgBr (1M, 12mmol) at 0° C. and then allowed the reaction mixture to stir at roomtemperature for 3 h. The mixture was poured into a cold saturated NH₄Clsolution and extracted with DCM. The organic layer was washed withbrine, dried over Na₂SO₄ and evaporated under reduced pressure.Purification by flash column chromatography (2% MeOH-DCM) afforded thetitle compound 17 (78%).

EXAMPLE 49

[0257]4N-(3-(1-(3-Fluorophenyl)ethylamino)propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine.

[0258] The title compound was prepared (291 mg, 100%) from5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (172 mg, 0.76 m.mol) and N-1-(1-(3-fluorophenyl)ethyl)propane-1,3-diamine (150 mg, 0.76mmol) by following the general procedure described for Preparation 6.

[0259]¹H NMR (400 MHz, CDCl₃): δ 8.35 (s, 1H), 7.25 (m, 1H), 7.05 (m,2H), 6.95 (m, 1H), 5.90 (bs, 1H), 3.60-3.80 (m, 3H), 2.85 (m, 2H), 2.80(m, 2H), 2.70 (m, 1H), 2.55 (m, 1H), 1.75-1.95 (m, 6H), 1.40 (d, 3H). MS(ESI) m/z: Calculated: 384.51; Observed: 385.1 (M⁺+1).

EXAMPLE 50

[0260] 4N-(3-(3-Fluorobenzylamino)propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine

[0261] The title compound was prepared (145 mg, 69%) from3N-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-4-yl)-1,3-diaminopropane(150 mg, 0.57 m. mol) and 3-fluorobenzaldehyde (70 mg, 0.57 mmol) byfollowing the general procedure described for Preparation 3. ¹H NMR (400MHz, CDCl₃): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H),6.20 (bs, 1H), 3.80 (s, 2H), 3.70 (m, 2H), 2.80 (m, 6H), 1.80 (m, 6H),1.70 (bs, 1H). MS (ESI) m/z: Calculated: 370.49; Observed: 371.1 (M⁺+1).

EXAMPLE 51

[0262]N-(3-(1-(3-fluorophenyl)ethylamino)propyl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine

[0263] The title compound was prepared (157 mg, 62%) from4-chloro-6-isobutylthieno[2,3-d]pyrimidine (150 mg, 0.662 m. mol) andN-1-(1-(3-fluorophenyl)ethyl)propane-1,3-diamine (130 mg, 0.662 m. mol)by following the general procedure described for Preparation 6. ¹H NMR(400 MHz, CDCl₃): δ 8.40 (s, 1H), 7.40 (m, 1H), 7.05 (m, 2H), 6.95 (m,1H), 6.75 (bs, 1H), 6.70 (s, 1H), 3.85 (m, 1H), 3.70 (m, 2H), 2.80 (m,1H), 2.70 (d, 2H), 2.65 (m, 1H), 1.95 (m, 1H), 1.85 (m, 2H), 1.45 (d,3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 386.53; Observed: 387.1(M⁺+1).

EXAMPLE 52

[0264]N-(1-(1-(2,4,6-trifluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin4-amine

[0265] The title compound was prepared (110 mg, 55%) from6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (130 mg,0.45 m. mol) and 1-(2,4,6-trifluorophenyl)ethyl methanesulfonate (228mg, 0.9 mmol) by following the general procedure described forPreparation 12. ¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 6.75 (s, 1H),6.65 (m, 2H), 4.95 (d, 1H), 4.15 9q, 1H), 4.05 (m, 1H), 3.00 (m, 2H),2.70 (d, 2H), 2.20 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H), 1.55 (d, 3H),1.25-1.65 (m, 2H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 448.55;Observed: 449.2 (M⁺+1).

EXAMPLE 53

[0266]N-(1-(1-(2,6-difluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine

[0267] The title compound was prepared (104 mg, 54%) from6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (130 mg,0.45 m. mol) and 1-(2,6-difluorophenyl)ethyl methanesulfonate (211 mg,0.9 mmol) by following the general procedure described for Preparation12. ¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 7.10 (m, 1H), 6.90 (m,2H),6.75 (s, 1H), 4.90 (d, 1H), 4.25 (q, 1H), 4.05 (m, 1H), 3.05 (m, 2H),2.70 (d, 2H), 2.15 (m, 1H), 2.10 (m, 3H), 1.95 (m, 1H), 1.40 (d, 3H),1.45-1.65 (m, 2H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 430.56;Observed: 431.2 (M⁺+1).

EXAMPLE 54

[0268]N-(1-(cyclohexylmethyl)piperidin-4-yl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine

[0269] The title compound was obtained in 28% yield following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.36(s, 1H), 5.36 (d, 1H), 4.22 (m, 1H), 2.80 (d, 2H), 2.44 (s, 3H), 2.41(s, 3H), 2.21-2.09 (m, 7H), 1.79-1.45 (m, 6H), 1.20 (m, 4H), 0.88 (m,2H); MS (ESI) m/z: Calculated for C₂₀H₃₁N₄S, 359.23; Observed: 359.2(M⁺+1).

EXAMPLE 55

[0270][1-(3-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0271] The title compound was obtained in 72% yield following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.35(s, 1H), 7.24-7.29 (m, 1H), 7.07 (d, 2H), 6.94 (t, 1H), 5.20 (s, 1H),4.22 (m, 1H), 3.52 (s, 2H), 2.77-2.89 (m, 6H), 2.26 (t, 2H), 2.12-2.08(m, 2H), 1.95-1.85 (m, 2H), 1.62-1.53 (m, 2H). MS (ESI) m/z: Calculated:396.5; Observed: 397.6 (M⁺+1).

EXAMPLE 56

[0272][1-(2-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0273] The title compound was obtained in 58% yield following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.34(s, 1H), 7.37 (t, 1H), 7.23-7.28 (m, 1H), 7.11 (t, 1H), 7.04 (t, 1H),5.18 (d, 1H), 4.21 (m, 1H), 3.63 (s, 2H), 2.78-2.85 (m, 6H), 2.34 (t,2H), 2.04-2.11 (m, 2H), 1.89-1.92 (m, 4H), 1.51-1.60 (m, 2H). MS (ESI)m/z: Calculated: 396.5; Observed: 397.6 (M⁺+1)

EXAMPLE 57

[0274][1-(2-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0275] The title compound was obtained in 58% yield following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.34(s, 1H), 7.37 (t, 1H), 7.23-7.28 (m, 1H), 7.11 (t, 1H), 7.04 (t, 1H),5.18 (d, 1H), 4.21 (m, 1H), 3.63 (s, 2H), 2.78-2.85 (m, 6H), 2.34 (t,2H), 2.04-2.11 (m, 2H), 1.89-1.92 (m, 4H), 1.51-1.60 (m, 2H). MS (ESI)m/z: Calculated: 396.5; Observed: 397.6 (M⁺+1).

EXAMPLE 58

[0276][1-(3-Cyano-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0277] The title compound was prepared in 68% yield in following theprocedure described in Preparation 11. ¹H NMR (400 MHz, CDCl₃): δ 8.35(s, 1H), 7.69 (s, 1H), 7.56 (d, 2H), 7.47 (t, 1H), 5.19 (d, 1H), 4.24(m, 1H), 3.56 (s, 2H), 2.92 (t, 2H), 2.81 (t, 4H), 2.28 (t, 2H),2.12-2.18 (m, 2H), 1.96-1.88 (m, 4H). MS (ESI) m/z: Calculated: 403.5;Observed: 404.3 (M⁺+1).

EXAMPLE 59

[0278]N-{1-(3-fluorophenyl)-(ethyl)piperedin-4-yl}thieno[2,3-d]pyrimidin-4-amine

[0279] The title compound was prepared in 70% yield in following theprocedure described in Preparation 11. ¹H NMR (400 MHz, CDCl₃): δ 8.35(s, 1H), 7.30-7.24 (m, 2H), 7.19-7.12 (m, 3H), 7.08 (t, 1H), 5.14 (d,1H), 4.60-4.50 (m, 1H), 4.12 (q, 1H), 3.50-3.37 (m, 4H), 2.18-2.04 (m,2H), 1.78-1.69 (d, 2H), 1.40 (d, 3H). MS (ESI) m/z: Calculated: 356.4;Observed: 357.2 (M⁺+1).

EXAMPLE 60

[0280]N-{1-[2-(3-fluorophenyl)propan-2yl]piperidin-4-yl}(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0281] The title compound was prepared in 78% yield in following theprocedure described as below (Scheme 3). ¹H NMR (400 MHz, CD₃OD):δ 7.94(s, 1H), 7.29-7.21 (m, 3H), 6.83 (t, 1H), 3.81-3.72 (m, 1H), 3.08-3.01(m, 2H), 2.81 (t, 2H), 2.36-2.20 (m, 4H), 1.96-1.95 (m, 4H), 1,31 (s,3H), 1.30 (s, 3H). MS (ESI) m/z: Calculated: 424.5; Observed: 425.1(M⁺+1).

EXAMPLE 61

[0282]N-{1-(3,5,difluorobenzyl)piperedin-4-yl}thieno[2,3-d]pyrimidin-4-amine

[0283] The title compound was prepared in 82% yield in following theprocedure described in Preparation 10. ¹H NMR (400 MHz, CDCL₃): δ 8.70(s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.22-7.14 (m, 3H), 4.66 (m, 1H),3.91 (s, 2H), 3.50-3.37 (m, 4H), 2.39-1.85 (d, 2H). MS (ESI) m/z:Calculated: 360.42; Observed: 361.1 (M⁺+1).

EXAMPLE 62

[0284](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(2,4,6-trifluoro-phenyl)(2-methylpropyl)-piperidin-4-yl]-aminehydrochloride

[0285] The title compound was prepared in 55% yield in following theprocedure described in Preparation 11. ¹H NMR (400 MHz, CDCl₃): δ 8.30(s, 1H), 7.33-7.25 (m, 1H), 7.01-6.93 (m, 3H), 5.16 (d, 1H), 4.194.10(m, 1H), 3.60-3.50 (m, 1H), 2.82-2.60 (m, 4H), 2.32-2.02 (m, 4H),1.88-1.75 (m, 9H), 1.59-1.40 (m, 2H), 1.22 (d, 3H), 1.20 (d, 2H). MS(ESI) m/z: Calculated: 452.6; Observed: 453.2 (M⁺+1).

EXAMPLE 63

[0286]{1-[1-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperidin-4-yl}-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0287] The title compound was prepared (97 mg, 81%) from(4-methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine(150 mg, 0.28 mmol) and methanesulfonic acid 1-(3-fluoro-phenyl)-ethylester (61.1 mg, 0.28 mmol) by following the procedure described forpreparation 12. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.38 (s, 1H), 7.20 (s,1H), 6.89-6.79 (m, 3H), 3.91 (q, 1H), 2.80-2.74(m, 4H), 2.20-2.09(M,2H), 1.90 (m, 2H), 1.89-1.85 (m, 4H), 1.55 (m, 4H), 1.31 (s, 3H); MS(SEI): m/z: Calculated: 424.2; Observed: 425.2 (M⁺+1).

EXAMPLE 64

[0288][1-(4-Methyl-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0289] The title compound was prepared in 82% yield in following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.40(s, 1H), 7.24-7.22 (d, 2H), 7.19-7.02 (d, 2H), 5.24 (d,1H), 4.26 (m,1H), 3.78 (s, 2H), 2.92-2.86 (m, 4H), 2.41 (s, 3H), 2.10-2.06 (m, 2H),2.04-1.92 (m, 2H), 1.90-1.81 (m, 4H), 1.69-1.57 (m, 4H). MS (ESI) m/z:Calculated: 392.56; Observed: 393.6 (M⁺+1).

EXAMPLE 65

[0290][1-(4-Methoxy-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0291] The title compound was prepared in 65% yield in following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.35(s, 1H), 7.09-7-6.94 (d, 2H), 6.92-6.02 (d, 2H), 5.21 (s,1H), 4.20 (m,1H), 3.77 (s, 3H), 3.52 (s, 2H), 2.89-2.77 (m, 2H), 2.79-2.61 (t, 2H),2.09-2.23 (m, 2H), 1.99-1.90 (m, 2H), 2.01-1.91 (m, 4H), 1.65-1.55 (m,4H). MS (ESI) m/z: Calculated: 408.5; Observed: 409.6 (M⁺+1).

EXAMPLE 66

[0292](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(4-trifluoromethoxy-benzyl)-piperidin-4-yl]-amine

[0293] The title compound was prepared in 42% yield in following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.66(s, 1H), 7.22-7.45 (m, 4H), 3.68 (s, 2H), 2.87-2.89 (m, 1H), 2.80-2.83(m, 4H), 2.10-2.25 (m, 2H), 1.91-1.93 (m, 2H), 1.82-1.85 (m, 4H),1.65-1.68 (m, 4H). MS (ESI) m/z: Calculated: 462.5; Observed: 463.4(M⁺+1).

EXAMPLE 67

[0294](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(3,4-methylenedioxy-benzyl)-piperidin-4-yl]-amine

[0295] The title compound was prepared in 55% yield in following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.40(s, 1H), 6.94 (d, 1H), 6.88-6.59 (m, 2H), 5.99 (s,1H), 5.20 (d, 1H),4.21 (m, 1H), 3.50 (s, 2H), 2.97-2.84 (m, 2H), 2.81-2.71 (t, 2H),2.29-2.13 (m, 2H), 2.05-1.96 (m, 2H), 1.91-1.82 (m, 4H), 1.62-1.50 (m,4H). MS (ESI) m/z: Calculated: 422.5; Observed: 423.3 (M⁺+1).

EXAMPLE 68

[0296]2-{4-(5,6-Dimethylthieno[2,3-d]pyrimidin-4-ylamino)piperedin-1-yl-methyl}benzonitrile

[0297] The title compound was prepared in 56% yield in following theprocedure described in Preparation 11. ¹H NMR (400 MHz, CDCl₃): δ8.35(s, 1H), 7.67-7.62 (m, 1H), 7.56-7.53 (m, 2H), 7.39-7.35 (m, 1H), 5.34(d, 1H), 4.26-4.23 (m, 1H), 3.74 (s, 2H), 2.92-2.84 (m, 4H), 2.44 (s,3H), 2.41 (s, 3H), 2.14-2.09 (m, 2H), 1.66-1.56 (m, 2H). MS (ESI) m/z:Calculated: 377.5; Observed: 378.1 (M⁺+1).

EXAMPLE 69

[0298](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(2,6-difluoro-phenylethyl)-piperidin-4-yl]-amine

[0299] The title compound was prepared in 52% yield in following theprocedure described in Preparation 11. ¹H NMR (400 MHz, CDCl₃): δ 8.30(s, 1H), 7.26-7.18 (m, 1H), 6.80 (t, 2H), 5.17 (d, 1H), 4.24 (q, 1H),4.154.11 (m, 1H), 2.90 (t, 2H), 2.70 (t, 2H), 2.36-2.11 (m, 4H),2.09-1.87 (m, 4H), 1.59 (d, 3H). MS (ESI) m/z: Calculated: 428.5;Observed: 429.1 (M⁺+1).

EXAMPLE 70

[0300](5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(2,4,6-trifluorophenylethyl)-piperidin-4-yl]-amine

[0301] The title compound was prepared in 56% yield in following theprocedure described in Preparation 11. ¹H NMR (400 MHz, CDCl₃): δ 8.31(s, 1H), 6.65 (t, 2H), 5.16 (d, 1H), 4.19-4.08 (m, 2H), 2.90-2.77 (m,4H), 2.33-2.07 (m, 4H), 1.89-1.85 (m, 4H), 1.60-1.56 (m, 4H), 1.40 (d,3H). MS (ESI) m/z: Calculated: 446 5; Observed: 447.2 (M⁺+1).

EXAMPLE 71

[0302](1-Naphthalen-2-ylmethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0303] The title compound was prepared in 35% yield in following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.38(s, 1H), 7.82-7.79 (m, 3H), 7.44-7.48 (m, 4H), 5.24 (d, 1H), 4.20 (m,1H), 3.64 (s, 2H), 2.83-2.85 (m, 1H), 2.77-2.80 (m, 4H), 2.08-2.21 (m,2H), 1.89-1.91 (m, 2H), 1.86-1.88 (m, 4H), 1.53-1.58 (m, 4H). MS (ESI)m/z: Calculated: 428.5; Observed: 429.8 (M⁺+1).

EXAMPLE 72

[0304][1-(2,2-Diphenyl-ethyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0305] The title compound was prepared in 46% yield in following theprocedure as described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.63(s, 1H), 7.76-7.74 (m, 6H), 7.40-7.42 (m, 4H), 4.85 (m, 1H), 3.01 (m,2H), 2.85-2.87 (m, 1H), 2.81-2.84 (m, 4H), 2.11-2.24 (m, 2H), 1.90-1.92(m, 2H), 1.81-1.84 (m, 4H), 1.66-1.69 (m, 4H). MS (ESI) m/z: Calculated:468.6; Observed: 469.8 (M⁺+1).

EXAMPLE 73

[0306][1-(4-Chloro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0307] The title compound was prepared in 82% yield in following theprocedure described in Preparation 6. ¹H NMR (400 MHz, CDCl₃): δ 8.35(s, 1H), 7.27-7.13 (m, 2H), 7.03-6.89 (m, 2H), 4.21 (m, 1H), 3.89 (s,2H), 3.21-3.14 (m, 2H), 2.90-2.74 (m, 8H), 2.02-1.92 (m, 4H), 1.64-1.51(m, 4H). MS (ESI) m/z: Calculated: 412.9; Observed: 413.7 (M⁺+1).

EXAMPLE 74

[0308]6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine

[0309] The title compound was prepared (289 mg, 64%) from tert-butyl4-(6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate(611 mg, 1.6 m. mol) by following the general procedure described forPreparation 10. ¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 5.30 (d, 1H),4.25 (m, 1H), 3.15 (m, 2H), 2.85 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H),1.95 (bs, 1H), 1.45 (m, 2H).

EXAMPLE 75

[0310]3-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-4-yl)-1,3-diaminopropane

[0311] A solution of4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (0.5 g,2.43 m. mol) in 1,3-diaminepropane (5 ml) was heated at 80° C. for 1day. It was cooled to room temperature and then diluted with water (50mL). The clear solution was cooled at 0° C. for over night. Theresulting solid was filtered and dried to get the title compound (0.3 g,52%) as a brown color solid. ¹H NMR (400 MHz, CD₃OD): δ 8.20 (s, 1H),3.65 (t, 2H), 2.95 (m, 2H), 2.80 (m, 4H), 1.80-2.00 (m, 6H). MS (ESI)m/z: Calculated: 262.37; Observed: 263.1 (M⁺+1).

EXAMPLE 76

[0312] 6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine

[0313] The title compound was prepared (628 mg, 94%) from tert-butyl4-(6-isobutylthieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate(900 mg, 2.3 m. mol) by following the general procedure described forPreparation 10. ¹H NMR (400 MHz, CDCl₃): δ 8.45 (s, 1H), 6.80 (s, 1H),4.95 (d, 1H), 4.30 (m, 1H), 3.20 (m, 2H), 2.85 (m, 2H), 2.75 (d, 2H),2.40 (bs, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.50 (m, 2H), 1.00 (d, 6H).

EXAMPLE 77

[0314]{(5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)}-piperidin-4-yl-amine

[0315]¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 5.09 (d, 1H), 4.28 (m,1H), 3.70 (t, 2H), 3.03 (t, 2H), 2.20-1.93 (m, 4H), 1.70-1.55 (m, 4H),1.59 (m, 4H). MS (ESI) m/z: Calculated: 288.4; Observed: 289.5 (M+1).

EXAMPLE 78

[0316] 1-(5,6-Dimethyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl-amine

[0317]¹H NMR (400 MHz, CDCl₃): δ 8.60 (s, 1H), 6.90 (s, 1H), 3.80 (d,2H), 3.00 (m, 5H), 2.49 (s, 3H), 2.47 (s, 3H), 2.00-1.80 (m, 4H). MS(ESI) m/z: Calculated: 262.3: Observed: 263.2 (M+1).

EXAMPLE 79

[0318] Thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl-amine

[0319]¹H NMR (400 MHz, CDCl₃): δ 8.46 s, 1H), 7.20 (dd, 2H), 3.10 (m,5H), 1.60 (m, 4H). MS (ESI) m/z: MS (ESI) m/z: Calculated: 234.3:Observed: 235.1 (M+1).

EXAMPLE 80

[0320](4-Methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine,diTFA salt

[0321] The title compound was prepared (179 mg, 97%) from4-methyl-4-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (140 mg, 0.35 mmol) by following the proceduredescribed for preparation 10. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.51 (sb,2H), 8.27 (s, 1H), 3.15 (m, 2H), 3.03 (m, 4H), 2.77 (m, 2H), 2.68 (m,2H), 1.82 (m, 6H), 1.51 (s, 3H); MS (SEI): m/z: Calculated: 302.2;Observed: 303.1 (M⁺+1).

EXAMPLE 81

[0322]tert-butyl-4-(6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate

[0323] The title compound was prepared (611 mg, 82%) from4,6-dichloro-5-methylthieno[2,3-d]pyrimidine (425 mg, 1.94 m. mol) andtert-butyl 4-aminopiperidine-1-carboxylate (582 mg, 2.9 m. mol) byfollowing the general procedure described for Preparation 9. ¹H NMR (400MHz, CDCl₃): δ 8.40 (s, 1H), 5.25 (d, 1H), 4.35 (m, 1H), 4.30 (m, 2H),3.00 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.45 (s, 9H), 1.35-1.55 (m,2H).

EXAMPLE 82

[0324] tert-butyl4-(6-isobutylthieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate

[0325] The title compound was prepared (337 mg, 65%) from4-chloro-6-isobutylthieno[2,3-d]pyrimidine (300 mg, 1.32 m. mol) andtert-butyl 4-aminopiperidine-1-carboxylate (400 mg, 1.99 m. mol) byfollowing the general procedure described for Preparation 9. ¹H NMR (400MHz, CDCl₃): δ 8.45 (s, 1H), 6.80 (s, 1H), 4.95 (m, 1H), 4.35 (m, 1H),4.15 (m, 2H), 2.95 (m, 2H), 2.75 9d, 2H), 2.15 (m, 2H), 1.95 (m, 1H),1.45 (s, 9H), 1.40-1.50 (m, 2H), 0.95 (d, 6H).

EXAMPLE 83

[0326] t-Butyl4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate

[0327] A mixture of t-butyl4-(thieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate 13 (1.00 g,3.00 mmol) and N-chlorosuccinimide (0.39 g, 3.00 mmol) were heated in 50mL of acetic acid for 3 h. After cooling to room temperature acetic acidwas removed under vacuum and the remaining residue was partition in 1NNaOH and DCM. The DCM was evaporated to collect 0.78 g of t-butyl4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylateafter purification by silica chromatography in 5% methanol in DCM (71%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.45 (s, 1H), 7.01 (s, 1H), 4.94 (d,1H), 4.32 (m, 1H), 4.15 (m, 2H), 2.94 (m, 2H), 2.11 (m, 2H), 1.48 (s,9H), 1.44 (m, 2H); MS (ESI) m/z: Calculated for C₁₆H₂₁ClN₄O₂S, 368.11;Observed: 368.8 (M⁺+1).

EXAMPLE 84

[0328]{(5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl}-piperidin-4-yl-carbamicacid tert-butyl ester

[0329]¹H NMR (400 MHz, CDCl₃): δ 8.51 (s, 1H), 5.12 (d, 1H), 4.32 (m,1H), 3.94 (t, 2H), 3.17 (t, 2H), 2.26-2.19 (m, 4H), 1.78-1.69 (m, 4H),1.61 (m, 4H), 1.43 (s, 9H). MS (ESI) m/z: Calculated: 362.4; Observed:363.5 (M+1).

EXAMPLE 85

[0330]{1-(5,6-Dimethylthieno[2,3-d]pyrimidin-4-yl)}-piperidin-4-yl-carbamicacid tert-butyl ester

[0331]¹H NMR (400 MHz, CDCl₃): δ 8.59 (s, 1H), 7.00 (s, 1H), 4.59 (br s,1H), 3.80 (m, 3H), 3.15 (t, 2H), 2.49 (s, 3H), 2.47 (s, 3H), 1.61 (m,4H), 1.49 (s, 9H). MS (ESI) m/z: Calculated: 388.5; Observed: 389.4(M+1).

EXAMPLE 86

[0332] Thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-yl-carbamic acidtert-butyl ester

[0333]¹H NMR (400 MHz, CDCl₃): δ 8.44 (s, 1H), 7.25 (dd, 2H), 4.45 (d,1H), 3.80 (m, 1H), 3.24 (m, 2H), 2.18 (m, 2H), 1.50 (m, 2H), 1.49 (s,9H). MS (ESI) m/z: Calculated: 334.4; Observed: 335.2 (M+1).

EXAMPLE 87

[0334]4-Methyl-4-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

[0335] The title compound was prepared (373.9 mg, 93%) from4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (224 mg, 1mmol) and 4-amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester(235.4 mg, 1.1 mmol) by following the procedure described forpreparation 9. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.39 (s, 1H), 3.33 (m,4H), 3.10 (m, 2H), 2.87 9M, 2H), 1.93 (m, 4H), 1.66 (m, 4H), 1.40 (s,9H), 1.22 (s, 3H); MS (SEI): m/z: Calculated: 402.6; Observed: 403.2(M⁺+1).

EXAMPLE 88

[0336] 1-(3-Fluoro-benzyl)-piperidin-4-ylamine trifluoroacetate salt

[0337] The compound was obtained in 90% yield following the proceduredescribed in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (bs, 2H),7.48 (q, 1H), 7.39-7.22 (m, 3H), 4.27 (s, 2H), 3.60-3.20 (m, 4H), 3.08(m, 1H), 2.18-2.08 (m, 2H), 1.90-1.79 (m, 2H). MS (ESI) m/z: Calculated:208.2; Observed: 209.2 (M⁺+1).

EXAMPLE 89

[0338] 1-(2-Fluoro-benzyl)-piperidin-4-ylamine trifluoroacetate salt

[0339] The compound was obtained in 85% yield following the proceduredescribed in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (bs, 2H),7.55-7.39 (m, 2H), 7.30-7.22 (m, 2H), 4.31 (s, 2H), 3.51-3.42 (m, 4H),3.11 (m, 1H), 2.19-2.10 (m, 2H), 1.95-1.75 (m, 2H). MS (ESI) m/z:Calculated: 208.2; Observed: 209.2 (M⁺+1).

EXAMPLE 90

[0340] 1-(4-Chloro-benzyl)-piperidin-4-ylamine trifluoroacetate salt

[0341] The compound was obtained in 86% yield following the proceduredescribed in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (bs, 2H),7.69 (d, 2H), 7.42 (d, 2H), 4.26 (s, 2H), 3.33-2.91 (m, 1H) 3.10-2.22(m, 4H), 2.21-1.89 (m, 4H). MS (ESI) m/z: Calculated: 224.7; Observed:225.6 (M⁺+1).

EXAMPLE 91

[0342] 4-(4-Aminopiperidin-4-yl)-methyl-benzonitrile trifluoroacetatesalt

[0343] The compound was obtained in 86% yield following the proceduredescribed in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (bs, 2H),7.61-7.50 (m, 2H), 7.44-7.32 (m, 2H), 4.29 (s, 2H), 3.62-3.49 (m, 4H),3.12 (m, 1H), 2.21-2.12 (m, 2H), 1.95-1.78 (m, 2H). MS (ESI) m/z:Calculated: 208.2; Observed: 209.2 (M⁺+1).

EXAMPLE 92

[0344] 1-(4-Toluyl)-piperidin-4-ylamine trifluoroacetate salt

[0345] The compound was obtained in 87% yield following the proceduredescribed in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (bs, 2H),7.68 (m, 2H), 7.28 (m, 2H), 4.21 (s, 2H), 3.2 (m, 1H) 3.08 (m, 4H), 2.76(s, 3H), 1.91-2.21 (m, 4H). MS (ESI) m/z: Calculated: 204.3; Observed:205.2 (M⁺+1).

EXAMPLE 93

[0346] 1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylaminetrifluoroacetate salt

[0347] The title compound was obtained in 70% following the proceduredescribed in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (bs, 2H),7.25 (s, 1H), 6.96-7.03 (m, 2H), 6.06 (s, 2H), 4.12 (s, 2H), 3.35 (m,1H), 3.22 (m, 2H), 2.93 (m, 2H), 1.96-2.1 (m, 4H). MS (ESI) m/z:Calculated: 234.2; Observed: 235.2 (M⁺+1).

EXAMPLE 94

[0348] 1-(4-Methoxy-benzyl)-piperidin-4-ylamine trifluoroacetate salt

[0349] The title compound was obtained in 83% yield following theprocedure described in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.44(bs, 2H), 7.25-7.19 (d, 2H), 7.20-7.09 (d, 2H), 4.29 (s, 2H), 3.50-3.41(m, 4H), 3.17 (m, 1H), 2.14-2.06 (m, 2H), 1.93-1.70 (m, 2H). LC/MS (ESI)m/z: Calculated: 220.6; Observed: 221.4 (M⁺+1).

EXAMPLE 95

[0350] 1-(4-Trifluoromethoxy-benzyl)-piperidin-4-ylaminetrifluoroacetate salt

[0351] The title compound was obtained in 63% yield following theprocedure described in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.41(bs, 2H), 7.39-7.23 (m, 2H), 7.22-7.10 (m, 2H), 4.33 (s, 2H), 3.49-3.35(m, 4H), 3.13 (m, 1H), 2.21-2.14 (m, 2H), 1.90-1.82 (m, 2H). LC/MS (ESI)m/z: Calculated: 274.1; Observed: 275.3 (M⁺+1).

EXAMPLE 96

[0352] 1-Naphthalen-2-ylmethyl-piperidin-4-ylamine trifluoroacetate salt

[0353] The compound was obtained in 91% yield following the proceduredescribed in Preparation 5. ¹H NMR (500 MHz, DMSO-d₆): δ 8.39 (bs, 2H),8.11 (m, 1H), 7.96 (m, 3H), 7.69 (m, 1H), 7.59 (m, 1H), 7.06 (d, 1H),4.40 (s, 2H), 3.43 (m, 1H), 3.08-3.17 (m, 4H), 1.7-1.9 (m, 4H). MS (ESI)m/z: Calculated: 240.3; Observed: 241.2 (M⁺+1).

EXAMPLE 97

[0354] 1-(2,2-Diphenyl-ethyl)-piperidin-4-ylamine trifluoroacetate salt

[0355] The title compound was obtained in 42% yield following theprocedure described in Preparation 5. LC/MS (ESI) m/z: Calculated:280.4; Observed: 281.3 (M⁺+1).

EXAMPLE 98

[0356] tert-Butyl-1-(2-fluorobenzyl)piperidin-4yl-carbamate

[0357] The compound was obtained in 92% yield following the proceduredescribed in Preparation 4. ¹H NMR (400 MHz, CDCl₃): δ 7.34-7.28 (m,2H), 7.02-6.94 (m, 2H), 4.21 (brs, 1H), 3.55 (s, 2H), 3.13 (t, 2H), 2.98(t, 2H) 2.08 (t, 2H), 2.00-1.98 (m, 2H), 1.44 (s, 9H). MS (ESI) m/z:Calculated: 308.8; Observed: 309.7 (M⁺+1).

EXAMPLE 99

[0358] tert-Butyl-1-(3-fluorobenzyl)piperidin-4yl-carbamate

[0359] The compound was obtained in 90% yield following the proceduredescribed in Preparation 4. ¹H NMR (400 MHz, CDCl₃): δ 7.22-7.10 (m,3H), 7.02-6.90 (m, 1H), 4.11 (brs, 1H), 3.43 (s, 2H), 3.00 (t, 2H), 2.92(t, 2H) 2.02 (t, 2H), 1.98-1.87 (m, 2H), 1.43 (s, 9H). MS (ESI) m/z:Calculated: 308.8; Observed: 309.5 (M⁺+1).

EXAMPLE 100

[0360] tert-Butyl-1-(4-fluorobenzyl)piperidin-4yl-carbamate

[0361] The compound was obtained in 92% yield following the proceduredescribed in Preparation 4. ¹H NMR (400 MHz, CDCl₃): δ 7.37-7.21 (m,2H), 7.00-6.88 (m, 2H), 4.02 (brs, 1H), 3.39 (s, 2H), 3.00 (t, 2H), 2.92(t, 2H) 2.02 (t, 2H), 1.98-1.87 (m, 2H), 1.43 (s, 9H). MS (ESI) m/z:Calculated: 308.8; Observed: 309.9 (M⁺+1).

EXAMPLE 101

[0362] 1-(3,5-difluorobenzyl)piperidin-4-amine

[0363] The title compound was prepared (1.92 g, 85%) from tert-butyl1-(3,5-difluorobenzyl)piperidin-4-ylcarbamate (3.26 g, 10 m. mol) byfollowing the general procedure described for Preparation 5. ¹H NMR (400MHz, CD₃OD): δ 6.90 (m, 2H), 6.75 (m, 1H), 3.50 (s, 2H), 3.15 (m, 1H),2.85 (m, 2H), 2.10 (m, 2H), 1.85 (m, 2H), 1.50 (m, 2H). MS (ESI) m/z:Calculated: 226.27; Observed: 227.1 (M⁺+1).

EXAMPLE 102

[0364] 1-(4-Fluoro-benzyl)-piperidin-4-ylamine trifluoroacetate salt

[0365] The compound was obtained in 87% yield following the proceduredescribed in Preparation 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (bs, 2H),7.68 (m, 2H), 7.28 (m, 2H), 4.21 (s, 2H), 3.2 (m, 1H) 3.08 (m, 4H),1.9-2.2 (m, 4H). MS (ESI) m/z: Calculated: 208.2; Observed: 209.2(M⁺+1).

EXAMPLE 103

[0366] N1-(1-(3-fluorophenyl)ethyl)propane-1,3-diamine

[0367] The title compound was prepared (0.66 g, 100%) from tert-butyl3-(1-(3-fluorophenyl)ethylamino)propylcarbamate (1 g, 3.38 m. mol) byfollowing the general procedure described for Preparation 10. ¹H NMR(400 MHz, CD₃OD): δ 7.35 (m, 1H), 7.15 (m, 2H), 6.95 (m, 1H), 3.75 (q,1H), 2.85 (m, 2H), 2.55 (m, 1H), 2.45 (m, 1H), 1.75 (m, 2H), 1.35 9d,3H). MS (ESI) m/z: Calculated: 196.26; Observed: 197.0 (M⁺+1).

EXAMPLE 104

[0368] tert-butyl 3-(1-(3-fluorophenyl)ethylamino)propylcarbamate

[0369] A solution of tert-butyl 3-aminopropylcarbamate (0.7 g, 4.05 m.mol) and 1-(3-fluorophenyl)ethanone (0.5 g, 3.6 m. mol) in titanium(IV)isopropoxide (1.8 mL, 6 m. mol) was stirred at room temperature for 3 h.It was diluted with methanol (10 mL) and then sodium borohydride (0.22g, 5.76 m. mol) was added carefully and stirred for 10 minutes. Thereaction mixture was quenched with 0.1 N NaOH (10 mL) solution. It wasfiltered through celite and washed with dichloromethane (2×20 mL). Theorganic layer was separated, dried over CaCl₂ and evaporated to get thetitle product (1.07 g, 100%) as thick liquid. ¹H NMR (400 MHz, CDCl₃): δ7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 5.10 (bs, 1H), 3.75 (q, 1H),3.15 (m, 2H), 2.55 (m, 1H), 2.45 (m, 1H), 1.60 (m, 2H), 1.45 (s, 9H),1.35 (d, 3H). MS (ESI) m/z: Calculated: 296.38; Observed: 297.0 (M⁺+1).

EXAMPLE 105

[0370] t-Butyl 1-(cyclohexylmethyl)piperidin-4-ylcarbamate

[0371] The title compound was obtained in 81% yield following theprocedure described in Preparation 3. ¹H NMR (400 MHz, CDCl₃): δ 4.80(bs, 1H), 3.71 (m, 1H), 3.63 (m, 2H), 2.53 (m, 2H), 2.43 (m, 2H),2.00-1.61 (m, 9H), 1.44 (s, 9H), 1.23 (m, 4H), 0.95 (m, 2H); MS (ESI)m/z: Calculated for C₁₇H₃₃N₂O₂, 297.25; Observed: 297.1 (M⁺+1).

EXAMPLE 106

[0372] 1-(cyclohexylmethyl)piperidin-4-amine, dihydrochloride

[0373] The title compound was obtained in 71% yield following theprocedure described in Preparation 5. ¹H NMR (400 MHz, MeOH-d⁴): δ 3.69(dt, 2H), 3.49 (m, 1H), 3.11 (t, 2H), 2.98 (d, 2H), 2.24 (m, 2H), 2.11(m, 2H), 1.90-1.70 (m, 4H), 1.43-1.19 (m, 4H), 1.06 (m, 2H); MS (ESI)m/z: Calculated for C₁₂H₂₅N₂, 197.2; Observed: 197.2 (M⁺+1).

EXAMPLE 107

[0374] tert-butyl 1-(3,5-difluorobenzyl)piperidin-4-ylcarbamate

[0375] The title compound was prepared (3.3 g, 100%) from tert-butylpiperidin-4-ylcarbamate (2 g, 10 m. mol) and 3,5-difluorobenzaldehyde(1.42 g, 10 mmol) by following the general procedure described forPreparation 3. ¹H NMR (400 MHz, CDCl₃): δ 6.85 (m, 2H), 6.65 (m, 1H),4.45 (bs, 1H), 3.50 (m, 1H), 3.05 (s, 2H), 2.75 (m, 2H), 2.10 (m, 2H),1.90 (m, 2H), 1.45 (m, 11H). MS (ESI) m/z: Calculated: 326.38; Observed:327.0 (M⁺+1).

EXAMPLE 108

[0376] 4-chloro-6-isopropylthieno[2,3-d]pyrimidine

[0377] The title compound was prepared (13 g, 80%) from6-isopropylthieno[2,3-d]pyrimidin-4-ol (15 g, 0.077 mol) by followingthe general procedure described for Preparation 2. ¹H NMR (400 MHz,CDCl₃): δ 8.80 (s, 1H), 7.10 (s, 1H), 3.30 (m, 1H), 1.45 (d, 6H). MS(ESI) m/z: Calculated: 212.7; Observed: 213.2 (M⁺+1).

EXAMPLE 109

[0378] 4-chloro-6-isobutylthieno[2,3-d]pyrimidine

[0379] The title compound was prepared (0.96 g, 88%) from 46-isobutylthieno[2,3-d]pyrimidin-4-ol (1 g, 4.8 m. mol) by following thegeneral procedure described for Preparation 2. ¹H NMR (400 MHz, CDCl₃):δ 8.95 (s, 1H), 7.10 (s, 1H), 2.80 (d, 2H), 2.05 (m, 1H), 1.05 (d, 6H).MS (ESI) m/z: Calculated: 226.73; Observed: 227.1 (M⁺+1).

EXAMPLE 110

[0380] 4-Chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine

[0381] The title compound was prepared (6.3 g, 90%) from5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol (6.5 g, 32mmol) by following the procedure described for preparation 2. ¹H NMR(400 MHz, CDCl₃): δ (ppm) 8.71 (s, 1H), 3.10 (m, 2H), 2.89 (m, 2H), 1.94(m, 4H); MS (SEI): m/z: Calculated: 224; Observed: 225 (M⁺+1).

EXAMPLE 111

[0382] 4-Chloro-5,6-dimethyl-thieno[2,3-d]pyrimidine

[0383]¹H NMR (400 MHz, CDCl₃): δ 8.81 (s, 1H), 7.23 (s, 1H), 2,67 (s,3H), 2.69 (s, 3H). MS (ESI) m/z: Calculated: 198.6; Observed: 199.5(M+1).

EXAMPLE 112

[0384] 4-Chloro-thieno[2,3-d]pyrimidine

[0385]¹H NMR (400 MHz, CDCl₃): δ 8.88 (s, 1H), 7.65 (d, 1H), 7.48 (d,1H). MS (ESI) m/z: Calculated: 170.6; Observed: 171.0 (M+1).

EXAMPLE 113

[0386] 4,6-dichloro-5-methylthieno[2,3-d]pyrimidine

[0387] The title compound was prepared (428 mg, 98%) from6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ol (400 mg, 2.0 m. mol) byfollowing the general procedure described for Preparation 2. ¹H NMR (400MHz, CDCl₃): δ 8.80 (s, 1H), 2.65 (s, 3H).

EXAMPLE 114

[0388] 6-isobutylthieno[2,3-d]pyrimidin-4-ol

[0389] The title compound was prepared (3.58 g, 82%) from ethyl2-amino-5-isobutylthiophene-3-carboxylate (4.68 g, 21 m. mol) byfollowing the general procedure described for Preparation 1. ¹H NMR (400MHz, CD₃OD): δ 8.50 (s, 1H), 7.20 (s, 1H), 2.80 (d, 2H), 1.95 (m, 1H),1.00 (d, 6H). MS (ESI) m/z: Calculated: 208.28; Observed: 209.2 (M⁺+1).

EXAMPLE 115

[0390] 6-isopropylthieno[2,3-d]pyrimidin-4-ol

[0391] The title compound was prepared (15 g, 70%) from ethyl2-amino-5-isopropylthiophene-3-carboxylate (23.5 g, 0.11 mol) byfollowing the general procedure described for Preparation 1. ¹H NMR (400MHz, CDCl₃): δ 8.40 (s, 1H), 7.10 (s, 1H), 3.00 (m, 1H), 1.40 (d, 6H).MS (ESI) m/z: Calculated: 194.25; Observed: 195.3 (M⁺+1).

EXAMPLE 116

[0392] 6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ol

[0393] To a solution of 5-methylthieno[2,3-d]pyrimidin-4-ol (2 g, 12 m.mol) in acetic acid (30 mL) at room temperature, chlorine gas wasbubbled for 3 h. The reaction mixture was stirred at same temperaturefor 2 days. The solvent was evaporated under reduced pressure at 40° C.and the residue was dissolved in ethyl acetate (30 mL) and washed withsat. NaHCO₃ solution (3×20 mL). The organic layer was dried over sodiumsulfate and evaporated to get the title compound as a pale yellow solid(2 g, 82%). ¹H NMR (400 MHz, CDCl₃ and CD₃OD): δ 7.90 (s, 1H), 2.55 (s,3H). MS (ESI) m/z: Calculated: 200.65; Observed: 201.3 (M⁺+1).

EXAMPLE 117

[0394] 6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ol

[0395] The title compound was prepared (3.38 g, 75%) from ethyl2-amino-5-chloro-4-methylthiophene-3-carboxylate (5 g, 27 m. mol) byfollowing the general procedure described for Preparation 1. ¹H NMR (400MHz, CD₃OD): δ 8.00 (s, 1H), 7.00 (s, 1H), 2.55 (s, 3H). MS (ESI) m/z:Calculated: 166.2; Observed: 167.1 (M⁺+1).

EXAMPLE 118

[0396] Thieno[2,3-d]pyrimidin-4-ol

[0397]¹H NMR (400 MHz, CDCl₃): δ 8.05 (s, 1H), 7.53 (dd, 1H), 7.33 (dd,1H). MS (ESI) m/z: Calculated: 152.1; Observed: 153.2 (M+1).

EXAMPLE 119

[0398] 5,6 Dimethyl-thieno[2,3-d]pyrimidin-4-ol

[0399]¹H NMR (400 MHz, CDCl₃):δ 8.00 (s, 1H), 2.63 (s, 3H), 2.61 (s,3H). MS (ESI) m/z: Calculated: 180.23; Observed: 181.1 (M+1)

EXAMPLE 120

[0400] 5,6,7,8-Tetrahydro-benzo[4,5]-thieno[2,3-d]pyrimidin-4-ol

[0401] The title compound was obtained in 92% following the proceduredescribed in Preparation 1. ¹H NMR (400 MHz, DMSO-d₆): δ 12.35 (bs, 1H),8.0 (s, 1H), 2.88 (t, 2H), 2.74 (t, 2H), 1.74-1.82 (m, 4H). MS (ESI)m/z: Calculated: 206.2; Observed: 207.2 (M⁺+1).

[0402] General Synthesis of piperidinylamino-thieno[2,3-d]pyrimidines

[0403] Ethyl 2-amino-3-carboxythiophene 2 is refluxed with ammoniumformate and formamide to give the cyclized intermediate 3 which is thentreated with thionyl chloride to afford the chloro derivative 4.Boc-protected aminopiperidine 5 is reductively alkylated with a varietyof arylaldehydes 6 to provide the corresponding intermediates 7.Deprotection of 7 with trifluoroacetic acid treatment yields the freeamine intermediate 8. Reflux of a mixture of the key intermediates 4 and8 in i-propanol or acetonitrile in the presence of triethylamine yieldsthe final compound 1.

[0404] The following compounds of the invention made by the abovesynthetic method are expected to also have good activity:

(5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(4-trifluoromethyl-benzyl)-piperidin-4-yl]-amine

[0405]

(1-Phenethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

[0406]

[1-(3-Phenyl-propyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amineEXAMPLE 121

[0407] Compound Activity

[0408] Compounds of the invention were made according to the respectivesyntheses noted above, and their activity and selectivity wasdetermined. These compounds were found to be active (e.g., atconcentrations from about 0.1 to about 10 μM) and selective 5-HT_(2B)modulators. Test data is shown in Table 1. The compounds accordingly areexpected to be useful as 5-HT_(2B) receptor modulators, e.g., in thetreatment of a wide variety of clinical conditions which arecharacterized by serotonin excess or absence, e.g., serotoninergichypofunction or hyperfunction. Such conditions include those notedabove, and conditions associated with vascular disorders, e.g., angina,migraine, pulmonary hypertension and systemic hypertension. TABLE 1Functional (Antagonist Rat Fundus) PK (% F) T_(1/2) (hr) T_(1/2) (hr)Structure Compound K₁ (nM) IC₅₀ (nM) rat rat* po rat iv

1 0.57 830 9.8 0.5 0.5

2 0.79

3 0.97 5300 3.9 0.45 0.5

4 2.3 100

5 2.64 1300

6 4

7 4.2 5700 2.8 0.4 0.2

8 4.6

9 7.8

10 13 110 1.50 1

11 14

12 15

13 17

14 18 1600 17.20 0.8 0.3

15 20

16 44

17 52

18 70

19 72

20 84

21 120

22 150

23 210

24 950

25 1200

26 1300

[0409] Equivalents

[0410] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of the invention and are covered by the followingclaims. Various substitutions, alterations, and modifications may bemade to the invention without departing from the spirit and scope of theinvention as defined by the claims. Other aspects, advantages, andmodifications are within the scope of the invention. The contents of allreferences, issued patents, and published patent applications citedthroughout this application are hereby incorporated by reference. Theappropriate components, processes, and methods of those patents,applications and other documents may be selected for the invention andembodiments thereof.

What is claimed is:
 1. A compound having the formula

wherein R₁ and R₂ are independently hydrogen; lower alkyl; C₁-C₆cycloalkyl or cycloheteroalkyl; halogen or halo-substituted alkyl; or R₁and R₂, taken together, form a C₅-C₇ cycloalkyl or cycloheteroalkylring; Cy is a single or conjugated substituted or unsubstitutedalicyclic or aromatic ring structure; and n is 0, 1, 2, 3, 4 or 5; andpharmaceutically acceptable salts and/or esters thereof.
 2. The compoundof claim 1, wherein R₁ and R₂, taken together, form a C₅-C₇ cycloalkylor cycloheteroalkyl ring.
 3. The compound of claim 2, wherein R₁ and R₂,taken together, form a cyclohexyl ring.
 4. The compound of claim 1,wherein n is 0, 1, 2 or
 3. 5. The compound of claim 1, wherein saidlower alkyl is C₁-C₅ alkyl.
 6. The compound of claim 1, wherein saidcompound is a 5-HT receptor antagonist.
 7. The compound of claim 6,wherein said compound is a 5-HT₂ receptor antagonist.
 8. The compound ofclaim 7, wherein said compound is a 5-HT_(2A, B or C) receptorantagonist.
 9. The compound of claim 7, wherein said compound is a5-HT_(2B) receptor antagonist.
 10. The compound of claim 1, wherein saidcompound is[1-(2-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.11. The compound of claim 1, wherein said compound is[1-(3-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.12. The compound of claim 1, wherein said compound is[1-(4-Fluoro-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.13. The compound of claim 1, wherein said compound is[1-(4-Methyl-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.14. The compound of claim 1, wherein said compound is(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.15. The compound of claim 1, wherein said compound is(5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(4-trifluoromethyl-benzyl)-piperidin-4-yl]-amine.16. The compound of claim 1, wherein said compound is(1-Benzhydryl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.17. The compound of claim 1, wherein said compound is(1-Naphthalen-2-ylmethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.18. The compound of claim 1, wherein said compound is(1-Phenethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.19. The compound of claim 1, wherein said compound is[1-(3-Phenyl-propyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.20. The compound of claim 1, wherein said compound is(5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(4-trifluoromethoxy-benzyl)-piperidin-4-yl]-amine.21. The compound of claim 1, wherein said compound is[1-(4-Methoxy-benzyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.22. A compound having the formula

wherein R₁ and R₂ are independently be hydrogen; lower alkyl, C₁-C₆cycloalkyl or cycloheteroalkyl; halogens or halo-substituted alkyl; orR₁ and R₂, taken together, form a C₅-C₇ cycloalkyl or cycloheteroalkylring; R₃ and R₄ are independently Ar which is a single or conjugatedsubstituted or unsubstituted aromatic ring structure; R₅ is H,(C₁-C₅)alkyl, (C₁-C₆)cycloalkyl, halogen substituted alkyl, NH₂, NHMe,NMe₂, NHEt, NH(Et)₂, NH(Pr), N(Pr)₂; and n is 0, 1, 2, 3, 4 or 5; andpharmaceutically acceptable salts and/or esters thereof.
 23. Apharmaceutical composition comprising the compound of claim 1 in anamount effective to treat depression.
 24. A pharmaceutical compositioncomprising the compound of claim 1 in an amount effective to treat a CNSdisorder.
 25. A pharmaceutical composition comprising the compound ofclaim 1 in an amount effective to treat migraine.
 26. A method oftreating depression, comprising administering to a patient in needthereof a pharmaceutical composition comprising the compound of claim 1in an amount effective to treat said depression.
 27. A method oftreating a CNS disorder, comprising administering to a patient in needthereof a pharmaceutical composition comprising the compound of claim 1in an amount effective to treat said CNS disorder.
 28. A method oftreating a CNS disorder, comprising diagnosing a patient in need oftreatment and administering to a patient in need thereof a therapyincluding a pharmaceutical composition comprising the compound of claim1 in an amount effective to treat said CNS disorder.
 29. A method oftreating pulmonary hypertension, comprising administering to a patientin need thereof a pharmaceutical composition comprising the compound ofclaim 1 in an amount effective to treat said pulmonary hypertension. 30.A method of treating pulmonary hypertension, comprising diagnosing apatient in need of treatment and administering to a patient in needthereof a therapy including a pharmaceutical composition comprising thecompound of claim 1 in an amount effective to treat said pulmonaryhypertension.
 31. A method of treating systemic hypertension, comprisingadministering to a patient in need thereof a pharmaceutical compositioncomprising the compound of claim 1 in an amount effective to treat saidsystemic hypertension.
 32. A method of treating systemic hypertension,comprising diagnosing a patient in need of treatment and administeringto a patient in need thereof a therapy including a pharmaceuticalcomposition comprising the compound of claim 1 in an amount effective totreat said systemic hypertension.